Tube feed packages and methods for using same

ABSTRACT

Nutritional compositions that mimic whole foods and methods of using the nutritional compositions are provided. The nutritional compositions may include an increased number and variety of fruits and vegetables, an increased variety of macronutrient sources and an increased amount of other components that are found in whole foods. The nutritional compositions may also include ethnicity-specific meals and organic ingredients and provide emotional appeal to the patient and/or the patient&#39;s caregiver. Methods of administering such nutritional compositions to patients in need of same are also provided.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a National Stage of International ApplicationNo. PCT/US2011/042152, filed on Jun. 28, 2011, which claims priority toU.S. Provisional Patent Application No. 61/359,184, filed Jun. 28, 2010,and U.S. Provisional Patent Application No. 61/451,272, filed Mar. 10,2011, the entire contents of which are being incorporated herein byreference.

SUMMARY

Nutritional compositions including whole foods are provided. Methods ofusing the nutritional compositions are also provided. In a generalembodiment, the present disclosure provides a nutritional composition(e.g., oral nutritional supplements, tube feed formulations, etc.)including at least five different processed whole food components; asource of protein, a source of fat, a source of carbohydrate, and asource of vitamins and minerals.

In an embodiment, the five different processed whole food components mayinclude 4 servings of fruits/vegetables and 1 serving of an animalsource.

In an embodiment, the nutritional composition includes at least six orseven different whole food components.

In an embodiment, the whole food components are selected from the groupconsisting of a processed fruit, a processed vegetable, a processedmeat, a processed grain, or combinations thereof. In an embodiment, thewhole food components need not be processed.

In an embodiment, the nutritional composition further includes at leastone of an herb, a spice and a flavoring.

In an embodiment, the protein is selected from the group consisting ofdairy based proteins, plant based proteins, animal based proteins,artificial proteins, or combinations thereof.

In an embodiment, the dairy based proteins are selected from the groupconsisting of casein, caseinates, casein hydrolysates, whey, wheyhydrolysates, milk protein concentrate, milk protein isolate, orcombinations thereof.

In an embodiment, the plant based proteins are selected from the groupconsisting of soy protein, pea protein, canola protein, wheat andfractionated wheat proteins, corn proteins, zein proteins, riceproteins, oat proteins, potato proteins, peanut proteins, proteinsderived from beans, lentils, buckwheat, pulses, or combinations thereof.

In an embodiment, the animal based proteins are selected from the groupconsisting of beef, poultry, fish, lamb, seafood, pork, egg, orcombinations thereof.

In an embodiment, the nutritional composition further includesphospholipids.

In an embodiment, the nutritional composition further includes aprebiotic selected from the group consisting of acacia gum, alphaglucan, arabinogalactans, beta glucan, dextrans, fructooligosaccharides,fucosyllactose, galactooligosaccharides, galactomannans,gentiooligosaccharides, glucooligosaccharides, guar gum, inulin,isomaltooligosaccharides, lactoneotetraose, lactosucrose, lactulose,levan, maltodextrins, milk oligosaccharides, partially hydrolyzed guargum, pecticoligosaccharides, resistant starches, retrograded starch,sialooligosaccharides, sialyllactose, soyoligosaccharides, sugaralcohols, xylooligosaccharides, their hydrolysates, or combinationsthereof.

In an embodiment, the nutritional composition further includes aprobiotic selected from the group consisting of probiotics includeAerococcus, Aspergillus, Bacteroides, Bifidobacterium, Candida,Clostridium, Debaromyces, Enterococcus, Fusobacterium, Lactobacillus,Lactococcus, Leuconostoc, Melissococcus, Micrococcus, Mucor, Oenococcus,Pediococcus, Penicillium, Peptostrepococcus, Pichia, Propionibacterium,Pseudocatenulatum, Rhizopus, Saccharomyces, Staphylococcus,Streptococcus, Torulopsis, Weissella, or combinations thereof.

In an embodiment, the nutritional composition further includes an aminoacid selected from the group consisting of alanine, arginine,asparagine, aspartate, citrulline, cysteine, glutamate, glutamine,glycine, histidine, hydroxyproline, hydroxyserine, hydroxytyrosine,hydroxylysine, isoleucine, leucine, lysine, methionine, phenylalanine,proline, serine, taurine, threonine, tryptophan, tyrosine, valine, orcombinations thereof.

In an embodiment, the nutritional composition further includes a sourceof ω-3 fatty acids selected from the group consisting of α-linolenicacid, docosahexaenoic acid, eicosapentaenoic acid, or combinationsthereof. The source of ω-3 fatty acids may be selected from the groupconsisting of fish oil, poultry, eggs, flax seed, walnuts, almonds,algae, krill, modified plants, or combinations thereof.

In an embodiment, the nutritional composition further includes anucleotide. The nucleotide may be selected from the group consisting ofa subunit of deoxyribonucleic acid, a subunit of ribonucleic acid, apolymeric form of deoxyribonucleic acid, a polymeric form of ribonucleicacid, yeast extract forms, or combinations thereof.

In an embodiment, the nutritional composition further includes aphytonutrient that is isolated from food or is present as part of thewhole food component provided in the tube feed formula (fruits,vegetables, grains). These may be flavanoids, carotenoids, alliedphenolic compounds, polyphenolic compounds, terpenoids, alkaloids,sulphur-containing compounds, or combinations thereof.

In an embodiment, the nutritional composition further includesingredients with antioxidant activities selected from the groupconsisting of herbs/spices/flavorings (garlic, cinnamon, ginseng,turmeric, curcumin, rosemary, mint, lemongrass, ginkgo, ginger, tea,vanilla extract), polyphenols, carotenoids, flavonoids, lignan, lutein,lycopene coenzyme Q10 (“CoQ10”), glutathione Goji (wolfberry),lactowolfberry, hesperidine, selenium, vitamin A, vitamin E, orcombinations thereof.

In an embodiment, the vitamins are selected from the group consisting ofvitamin A, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3(niacin or niacinamide), vitamin B5 (pantothenic acid), vitamin B6(pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride),vitamin B7 (biotin), vitamin B9 (folic acid), and vitamin B 12 (variouscobalamins; commonly cyanocobalamin in vitamin supplements), vitamin C,vitamin D, vitamin E, vitamin K, folic acid, biotin, choline, orcombinations thereof.

In an embodiment, the minerals are selected from the group consisting ofboron, calcium, chromium, copper, iodine, iron, magnesium, manganese,molybdenum, nickel, phosphorus, potassium, selenium, silicon, tin,vanadium, zinc, or combinations thereof.

In an embodiment, the nutritional composition further includes anutrient source that is typically consumed by individuals in a specificregion of the world. For example, the nutrient source may be a fruit, avegetable, protein, an herb, a spice, a flavoring, or combinationsthereof.

In an embodiment, the nutritional composition includespediatric-friendly food blends, or foods that parents would consider“normal” for kids consuming an oral diet. Popular branded foods include,for example, Cheerios®, Juicy Juice®, Campbell's Alphabet Soup™, chickennuggets, strawberry shortcake, bananas, apple sauce, etc.

In an embodiment, the whole food components (e.g., fruit, vegetable,grain), vitamins, minerals, proteins, fats, and/or carbohydrates areorganic. In one embodiment, the protein source may be raised withnatural farming practices including free range (chicken), lamb and grassgrazing (beef).

In an embodiment, the nutritional composition includes a source of fiberor a blend of different types of fiber. The fiber blend may contain amixture of soluble and insoluble fibers. Soluble fibers may include, forexample, fructooligosaccharides, acacia gum, inulin, etc. Insolublefibers may include, for example, pea outer fiber.

In another embodiment, the nutritional composition includes a processedwhole food, at least seven different sources of macronutrients selectedfrom the group consisting of protein, carbohydrate, fat, or combinationsthereof, and a source of vitamins or minerals. The sources ofmacronutrients may be selected from fats, carbohydrates and proteins.

In an embodiment, the at least seven different sources of macronutrientsinclude at least one protein, at least one carbohydrate and at least onefat.

In an embodiment, the at least seven different sources of macronutrientsinclude at least three different protein sources.

In an embodiment, the at least seven different sources of macronutrientsinclude at least three different carbohydrate sources.

In an embodiment, the at least seven different sources of macronutrientsinclude at least three different fat sources.

In yet another embodiment, a method of improving the overall health of apatient having an underlying medical condition is provided. The methodincludes administering to a patient having an underlying medicalcondition a nutritional composition having at least five different wholefood components; a source of protein, a source of fat, carbohydrate, anda source of vitamins and minerals.

In an embodiment, the nutritional composition includes at least six orseven different whole food components.

In an embodiment, the whole food components are selected from the groupconsisting of a processed fruit, a processed vegetable, a processedmeat, a processed grain, a herb, spice or flavoring, or combinationsthereof.

In an embodiment, the patient uses the nutritional composition for along-term to receive nutrients found in whole food. The patient may besedentary/bedridden and/or may be an older adult. The patient may havedepressed or altered immune function and increased oxidative stress,compromised gut health, altered glucose metabolism and lipid status,poor musculoskeletal health (loss of bone and muscle), pressure ulcers,and chronic wounds. In an embodiment, the patient may also have anunderlying medical condition selected from the group consisting ofcerebral palsy, failure-to-thrive, cystic fibrosis, neuromusculardisorders, brain injury, developmental delay, or combinations thereof.

In another embodiment, a method of maintaining or improving the overallhealth of a patient using a tube feeding or nutritional composition fora long-term or having an underlying medical condition is provided. Themethod includes administering to a patient having an underlying medicalcondition a nutritional composition having a processed whole food, asource of vitamins or minerals, and at least seven different sources ofmacronutrients selected from the group consisting of protein,carbohydrates, fats, or combinations thereof.

In an embodiment, the nutritional composition contains at least sevendifferent sources of macronutrients with the sources including at leastone source of protein, at least one source of carbohydrate, and at leastone source of fat. The nutritional composition may also include a sourceof fiber. The nutritional composition may contain at least sevendifferent sources of macronutrients that may also include at least threedifferent proteins. The nutritional composition may contain at leastseven different sources of macronutrients that may also include at leastthree different carbohydrates. The nutritional composition may containat least seven different sources of macronutrients that may also includeat least three different fats. The nutritional composition may alsoinclude at least three different sources of fiber.

In another embodiment, methods of administering nutritional compositionare provided. The methods include administering a nutritionalcomposition as a bolus, at three or more different times per day. Thefirst nutritional composition having a whole food to a patient at afirst time of a day may correspond to a typical breakfast time,administering a second nutritional composition having a whole food tothe patient at a second time of the day may correspond to a typicallunch time, and administering a third nutritional composition having awhole food to the patient at a third time of the day may correspond to atypical dinner time. Additional bolus tube feeding may correspond tosnack times. As such, the present methods may include fourth, fifth orsixth nutritional compositions corresponding to typical daily snacktimes.

In an embodiment, the nutritional compositions are changed to a newnutritional composition on a daily basis. The nutritional compositionsmay also be changed to a new nutritional composition on a weekly ormonthly basis. The cycle of different nutritional compositions may occurby different weeks. In these respects, for example, the methods mayprovide a new first, or breakfast, formulation each day of the week. Themethods may also provide a new second, or lunch, formulations each dayof the week. In another embodiment, the nutritional composition may bethe same for each of breakfast, lunch and dinner for a first week, andthen changed to a second formulation for each of breakfast, lunch anddinner for a second week, etc.

In an embodiment, the first, second and third nutritional compositionsinclude at least one source of protein, at least one source ofcarbohydrate, at least one source of fat, and at least one type of fruitand vegetable. The protein of each of each of the first, second andthird nutritional compositions may be different. At least one of a fruitand a vegetable of each of the first, second and third nutritionalcompositions may be different.

In an embodiment, the nutritional composition may contain foodcomponents specific to cultures/regions of the world (e.g.,Mediterranean, Asia, South and Latin America).

In an embodiment, the amount/bolus of nutrients provided at a singletime point (resulting in a more concentrated dose) may elicit differentphysiological responses compared to when provided as a continuous feed.As an example, pulse feeding of protein stimulates protein synthesis toa greater extent than when protein is consumed evenly throughout theday. In an embodiment, at least one tube feeding formulation per day maycontain high amounts of protein.

In an embodiment, increased variety of foods and/or food components andflavors may be delivered to stimulate specific taste receptors in thegut, thus eliciting different physiological responses. For example,stimulation of the Umami taste receptor in the gut increases mucoussecretion and GLP-1 and GLP-2 release. Stimulation of the bitter tastereceptor in the gut increases CCK release and delays gastric emptying.Stimulation of the sweet taste receptor in the gut stimulates release ofGLP-1 and GIP, and also regulates the expression of glucose transporterthus enhancing gut absorption of sugars.

In an embodiment, the nutritional compositions may be delivered warm orcold. It can be theorized that differences in food temperature mayimpact digestion and physiological response.

In yet another embodiment, a tube feed package is provided. The packageincludes a first component contained in the package that is a tube feedformulation having a processed whole food, and a second componentcontained in the package, the second component being ingestible andpackaged separately from the first component. The second component mayinclude a taste, or an aroma that may stimulate the cephalic phase ofdigestion, and/or include functional ingredients such as probiotics fororal health.

In an embodiment, the second component is a tablet, lozenge, dissolvablestrip, or chewing gum that contains a flavor and scent, and may or maynot contain a source of protein, a source of fat or a source ofcarbohydrate. The tablet, lozenge, dissolvable strip or chewing gumwould simulate the experience of eating and stimulate the cephalicresponse, which primes the body to absorb and use nutrients. The secondcomponent may be compliant with a nothing per orem (“NPO”) diet. Thesecond component may also be calorie free and may also have a scratchand sniff component. The second component may release a scent uponopening.

In an embodiment, the flavor of the second component corresponds to theprocessed whole food of the tube feed formulation. The flavor and/orscent of the second component may also correspond to a nutrient sourcethat is typically consumed by individuals in a specific region of theworld.

In an embodiment, the second component includes a functional ingredientselected from the group consisting of probiotics, capsaisin, a source ofstrong flavor, or combinations thereof. The second component may have astrong flavor (e.g., tart, ginger, etc. to stimulate saliva production),and contain functional ingredients such as probiotics (to maintainhealthy oral flora), and/or ingredients that trigger the swallow reflexsuch as capsaicin. The second component may be, or have a, scratch andsniff component to enhance the aroma, and may be used when oral intakeis contraindicated (e.g., dysphagia, neurological impairment).

In an embodiment, the flavor and scent of the second component may ormay not be similar to the foods present in the tube feeding. In anotherembodiment, the second component comes with a variety of flavors foremotional appeal such that the patient can choose what they are hungryfor.

In an embodiment, the first and second components are contained in apackage having a shape of an eating utensil (e.g., a plate) withpictures or shapes of food components found in the tube feed formula, orcombinations thereof.

An advantage of the present disclosure is to provide improved tube feedformulations.

Another advantage of the present disclosure is to provide improvednutritional compositions that include real or whole foods.

Yet another advantage of the present disclosure is to providenutritional compositions that promote bone health.

Still yet another advantage of the present disclosure is to providenutritional compositions that preserve lean body mass.

Still yet another advantage of the present disclosure is to providenutritional compositions that preserve muscle mass.

Another advantage of the present disclosure is to provide nutritionalcompositions that maintain glucose homeostasis.

Another advantage of the present disclosure is to provide nutritionalcompositions that maintain normal or reduce cholesterol or triglycerideslevels.

Another advantage of the present disclosure is to provide nutritionalcompositions that maintain gut health.

Another advantage of the present disclosure is to provide nutritionalcompositions that help maintain healthy immune function and reduceoxidative stress.

Another advantage of the present disclosure is to provide nutritionalcompositions that support normal growth.

Another advantage of the present disclosure is to provide nutritionalcompositions that treat and/or prevent chronic diseases.

Yet another advantage of the present disclosure is to providenutritional compositions that treat and/or prevent pressure ulcers.

An advantage of the present disclosure is to provide nutritionalcompositions that improve the overall health of patients on a long-termtube feeding regimen. These patients may be sedentary, elderly, or havecystic fibrosis, quadriplegia, cerebral palsy, and/or otherneuromuscular disorders, or dysphagia.

Still yet another advantage of the present disclosure is to provide tubefeed formulations that provide emotional appeal to patients and/or theircaregivers.

Another advantage of the present disclosure is to provide tube feedformulations that mimic a real food, oral diet.

Yet another advantage of the present disclosure is to provide methods ofadministering tube feed formulations that simulate administration ofnormal meals.

Additional features and advantages are described herein, and will beapparent from the following Detailed Description.

DETAILED DESCRIPTION

As used herein, “about” is understood to refer to numbers in a range ofnumerals. Moreover, all numerical ranges herein should be understood toinclude all integer, whole or fractions, within the range.

As used herein the term “amino acid” is understood to include one ormore amino acids. The amino acid can be, for example, alanine, arginine,asparagine, aspartate, citrulline, cysteine, glutamate, glutamine,glycine, histidine, hydroxyproline, hydroxyserine, hydroxytyrosine,hydroxylysine, isoleucine, leucine, lysine, methionine, phenylalanine,proline, serine, taurine, threonine, tryptophan, tyrosine, valine, orcombinations thereof.

As used herein, “animal” includes, but is not limited to, mammals, whichinclude but is not limited to, rodents, aquatic mammals, domesticanimals such as dogs and cats, farm animals such as sheep, pigs, cowsand horses, and humans. Wherein the terms “animal” or “mammal” or theirplurals are used, it is contemplated that it also applies to any animalsthat are capable of the effect exhibited or intended to be exhibited bythe context of the passage.

As used herein, the term “antioxidant” is understood to include any oneor more of various substances such as beta-carotene (a vitamin Aprecursor), vitamin C, vitamin E, and selenium) that inhibit oxidationor reactions promoted by Reactive Oxygen Species (“ROS”) and otherradical and non-radical species. Additionally, antioxidants aremolecules capable of slowing or preventing the oxidation of othermolecules. Non-limiting examples of antioxidants include astaxanthin,carotenoids, coenzyme Q10 (“CoQ10”), flavonoids, glutathione Goji(wolfberry), hesperidine, lactowolfberry, lignan, lutein, lycopene,polyphenols, selenium, vitamin A, vitamin C, vitamin E, zeaxanthin, orcombinations thereof.

As used herein, “complete nutrition” includes nutritional products andcompositions that contain sufficient types and levels of macronutrients(protein, fats and carbohydrates) and micronutrients to be sufficient tobe a sole source of nutrition for the animal to which it is beingadministered to. Patients can receive 100% of their nutritionalrequirements from such complete nutritional compositions.

As used herein, “effective amount” is an amount that prevents adeficiency, treats a disease or medical condition in an individual or,more generally, reduces symptoms, manages progression of the diseases orprovides a nutritional, physiological, or medical benefit to theindividual. A treatment can be patient- or doctor-related.

While the terms “individual” and “patient” are often used herein torefer to a human, the invention is not so limited. Accordingly, theterms “individual” and “patient” refer to any animal, mammal or humanhaving or at risk for a medical condition that can benefit from thetreatment.

As used herein, non-limiting examples of sources of ω-3 fatty acids suchα-linolenic acid (“ALA”), docosahexaenoic acid (“DHA”) andeicosapentaenoic acid (“EPA”) include fish oil, poultry, eggs, or otherplant or nut sources such as flax seed, walnuts, almonds, algae, krill,modified plants, etc.

As used herein, “food grade micro-organisms” means micro-organisms thatare used and generally regarded as safe for use in food.

As used herein, “incomplete nutrition” includes nutritional products orcompositions that do not contain sufficient levels of macronutrients(protein, fats and carbohydrates) or micronutrients to be sufficient tobe a sole source of nutrition for the animal to which it is beingadministered to. Partial or incomplete nutritional compositions can beused as a nutritional supplement.

As used herein, “long term administrations” are preferably continuousadministrations for more than 6 weeks. Alternatively, “short termadministrations,” as used herein, are continuous administrations forless than 6 weeks.

As used herein, “mammal” includes, but is not limited to, rodents,aquatic mammals, domestic animals such as dogs and cats, farm animalssuch as sheep, pigs, cows and horses, and humans. Wherein the term“mammal” is used, it is contemplated that it also applies to otheranimals that are capable of the effect exhibited or intended to beexhibited by the mammal.

The term “microorganism” is meant to include the bacterium, yeast and/orfungi, a cell growth medium with the microorganism, or a cell growthmedium in which microorganism was cultivated.

As used herein, the term “minerals” is understood to include boron,calcium, chromium, copper, iodine, iron, magnesium, manganese,molybdenum, nickel, phosphorus, potassium, selenium, silicon, tin,vanadium, zinc, or combinations thereof.

As used herein, “normal bone growth” refers to the process by whichchildhood and adolescent bones are sculpted by modeling, which allowsfor the formation of new bone at one site and the removal of old bonefrom another site within the same bone. This process allows individualbones to grow in size and to shift in space. During childhood bones growbecause resorption (the process of breaking down bone) occurs inside thebone while formation of new bone occurs on its outer (periosteal)surface. At puberty the bones get thicker because formation can occur onboth the outer and inner (endosteal) surfaces. The remodeling processoccurs throughout life and becomes the dominant process by the time thatbone reaches its peak mass (typically by the early 20 s). In remodeling,a small amount of bone on the surface of trabeculae or in the interiorof the cortex is removed and then replaced at the same site. Theremodeling process does not change the shape of the bone, but it isnevertheless vital for bone health. Modeling and remodeling continuethroughout life so that most of the adult skeleton is replaced aboutevery 10 years. While remodeling predominates by early adulthood,modeling can still occur particularly in response to weakening of thebone.

As used herein, a “nucleotide” is understood to be a subunit ofdeoxyribonucleic acid (“DNA”) or ribonucleic acid (“RNA”). It is anorganic compound made up of a nitrogenous base, a phosphate molecule,and a sugar molecule (deoxyribose in DNA and ribose in RNA). Individualnucleotide monomers (single units) are linked together to form polymers,or long chains. Exogenous nucleotides are specifically provided bydietary supplementation. The exogenous nucleotide can be in a monomericform such as, for example, 5′-Adenosine Monophosphate (“5′-AMP”),5′-Guanosine Monophosphate (“5′-GMP”), 5′-Cytosine Monophosphate(“5′-CMP”), 5′-Uracil Monophosphate (“5′-UMP”), 5′-Inosine Monophosphate(“5′-IMP”), 5′-Thymine Monophosphate (“5′-TMP”), or combinationsthereof. The exogenous nucleotide can also be in a polymeric form suchas, for example, an intact RNA. There can be multiple sources of thepolymeric form such as, for example, yeast RNA.

“Nutritional products,” or “nutritional compositions,” as used herein,are understood to include any number of optional additional ingredients,including conventional food additives, for example one or more,acidulants, additional thickeners, buffers or agents for pH adjustment,chelating agents, colorants, emulsifies, excipient, flavor agent,mineral, osmotic agents, a pharmaceutically acceptable carrier,preservatives, stabilizers, sugar, sweeteners, texturizers, and/orvitamins. The optional ingredients can be added in any suitable amount.

As used herein the term “patient” is understood to include an animal,especially a mammal, and more especially a human that is receiving orintended to receive treatment, as it is herein defined.

As used herein, “phytochemicals” or “phytonutrients” are non-nutritivecompounds that are found in many foods. Phytochemicals are functionalfoods that have health benefits beyond basic nutrition, and are healthpromoting compounds that come from plant sources. Non-limiting examplesof phytonutrients, or phytochemicals, include those that are flavonoidsand allied phenolic and polyphenolic compounds, terpenoids such ascarotenoids, alkaloids and sulphur-containing compounds; includingcurcumin, limonin, and quercetin or combinations thereof.

As used in this disclosure and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a polypeptide”includes a mixture of two or more polypeptides, and the like.

As used herein, a “prebiotic” is a food substance that selectivelypromotes the growth of beneficial bacteria or inhibits the growth ormucosal adhesion of pathogenic bacteria in the intestines. They are notinactivated in the stomach and/or upper intestine or absorbed in the GItract of the person ingesting them, but they are fermented by thegastrointestinal microflora and/or by probiotics. Prebiotics are, forexample, defined by Glenn R. Gibson and Marcel B. Roberfroid, DietaryModulation of the Human Colonic Microbiota: Introducing the Concept ofPrebiotics, J. Nutr. 1995 125: 1401-1412 (1995). Non-limiting examplesof prebiotics include acacia gum, alpha glucan, arabinogalactans, betaglucan, dextrans, fructooligosaccharides, fucosyllactose,galactooligosaccharides, galactomannans, gentiooligosaccharides,glucooligosaccharides, guar gum, inulin, isomaltooligosaccharides,lactoneotetraose, lactosucrose, lactulose, levan, maltodextrins, milkoligosaccharides, partially hydrolyzed guar gum, pecticoligosaccharides,resistant starches, retrograded starch, sialooligosaccharides,sialyllactose, soyoligosaccharides, sugar alcohols,xylooligosaccharides, or their hydrolysates, or combinations thereof.

As used herein, probiotic micro-organisms (hereinafter “probiotics”) arefood-grade microorganisms (alive, including semi-viable or weakened,and/or non-replicating), metabolites, microbial cell preparations orcomponents of microbial cells that could confer health benefits on thehost when administered in adequate amounts, more specifically, thatbeneficially affect a host by improving its intestinal microbialbalance, leading to effects on the health or well-being of the host.See, Salminen S, Ouwehand A. Benno Y. et al., Probiotics: how shouldthey be defined?, Trends Food Sci. Technol. 1999:10, 107-10 (1999). Ingeneral, it is believed that these micro-organisms inhibit or influencethe growth and/or metabolism of pathogenic bacteria in the intestinaltract, and may also influence the microflora in the mouth. Theprobiotics may also activate the immune function of the host. For thisreason, there have been many different approaches to include probioticsinto food products. Non-limiting examples of probiotics includeAerococcus, Aspergillus, Bacteroides, Bifidobacterium, Candida,Clostridium, Debaromyces, Enterococcus, Fusobacterium, Lactobacillus,Lactococcus, Leuconostoc, Melissococcus, Micrococcus, Mucor, Oenococcus,Pediococcus, Penicillium, Peptostrepococcus, Pichia, Propionibacterium,Pseudocatenulatum, Rhizopus, Saccharomyces, Staphylococcus,Streptococcus, Torulopsis, Weissella, or combinations thereof.

As used herein, a “processed whole food” is a whole food that has beenmodified from its natural or prepared state and is in a state so that itcan be placed into a tube feed formulation.

The terms “protein,” “peptide,” “oligopeptides” or “polypeptide,” asused herein, are understood to refer to any composition that includes, asingle amino acid (monomers), two or more amino acids joined together bya peptide bond (dipeptide, tripeptide, or polypeptide), collagen,precursor, homolog, analog, mimetic, salt, prodrug, metabolite, orfragment thereof or combinations thereof. For the sake of clarity, theuse of any of the above terms is interchangeable unless otherwisespecified. It will be appreciated that polypeptides (or peptides orproteins or oligopeptides) often contain amino acids other than the 20amino acids commonly referred to as the 20 naturally occurring aminoacids, and that many amino acids, including the terminal amino acids,may be modified in a given polypeptide, either by natural processes suchas glycosylation and other post-translational modifications, or bychemical modification techniques which are well known in the art. Amongthe known modifications which may be present in polypeptides of thepresent invention include, but are not limited to, acetylation,acylation, ADP-ribosylation, amidation, covalent attachment of aflavanoid or a heme moiety, covalent attachment of a polynucleotide orpolynucleotide derivative, covalent attachment of a lipid or lipidderivative, covalent attachment of phosphatidylinositol, cross-linking,cyclization, disulfide bond formation, demethylation, formation ofcovalent cross-links, formation of cystine, formation of pyroglutamate,formylation, gamma-carboxylation, glycation, glycosylation,glycosylphosphatidyl inositol (“GPI”) membrane anchor formation,hydroxylation, iodination, methylation, myristoylation, oxidation,proteolytic processing, phosphorylation, prenylation, racemization,selenoylation, sulfation, transfer-RNA mediated addition of amino acidsto polypeptides such as arginylation, and ubiquitination. The term“protein” also includes “artificial proteins” which refers to linear ornon-linear polypeptides, consisting of alternating repeats of a peptide.

Non-limiting examples of sources of proteins include dairy basedproteins, plant based proteins, animal based proteins and artificialproteins. Dairy based proteins include, for example, casein, caseinhydrolysates, caseinates (e.g., all forms including sodium, calcium,potassium caseinates), whey hydrolysates, whey (e.g., all formsincluding concentrate, isolate, demineralized), milk proteinconcentrate, and milk protein isolate. Plant based proteins include, forexample, soy protein (e.g., all forms including concentrate andisolate), pea protein (e.g., all forms including concentrate andisolate), canola protein (e.g., all forms including concentrate andisolate), other plant proteins that commercially are wheat andfractionated wheat proteins, corn and it fractions including zein, rice,oat, potato, peanut, and any proteins derived from beans, buckwheat,lentils, and pulses. Animal based proteins may include, for example,beef, poultry, fish, lamb, seafood, pork, egg, or combinations thereof.

All dosage ranges contained within this application are intended toinclude all numbers, whole or fractions, contained within said range.

As used herein, a “synbiotic” is a supplement that contains both aprebiotic and a probiotic that work together to improve the microfloraof the intestine.

As used herein, the terms “treatment,” “treat” and “to alleviate”include both prophylactic or preventive treatment (that prevent and/orslow the development of a targeted pathologic condition or disorder) andcurative, therapeutic or disease-modifying treatment, includingtherapeutic measures that cure, slow down, lessen symptoms of, and/orhalt progression of a diagnosed pathologic condition or disorder; andtreatment of patients at risk of contracting a disease or suspected tohave contracted a disease, as well as patients who are ill or have beendiagnosed as suffering from a disease or medical condition. The termdoes not necessarily imply that a subject is treated until totalrecovery. The terms “treatment” and “treat” also refer to themaintenance and/or promotion of health in an individual not sufferingfrom a disease but who may be susceptible to the development of anunhealthy condition, such as nitrogen imbalance or muscle loss. Theterms “treatment,” “treat” and “to alleviate” are also intended toinclude the potentiation or otherwise enhancement of one or more primaryprophylactic or therapeutic measure. The terms “treatment,” “treat” and“to alleviate” are further intended to include the dietary management ofa disease or condition or the dietary management for prophylaxis orprevention a disease or condition.

As used herein, a “tube feed” is a complete or incomplete nutritionalproduct or composition that is administered to an animal'sgastrointestinal system, other than through oral administration,including but not limited to a nasogastric tube, orogastric tube,gastric tube, jejunostomy tube (“J-tube”), percutaneous endoscopicgastrostomy (“PEG”), port, such as a chest wall port that providesaccess to the stomach, jejunum and other suitable access ports.

As used herein the term “vitamin” is understood to include any ofvarious fat-soluble or water-soluble organic substances non-limitingexamples include choline, vitamin A, vitamin B1 (thiamine), vitamin B2(riboflavin), vitamin B3 (niacin or niacinamide), vitamin B5(pantothenic acid), vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine,or pyridoxine hydrochloride), vitamin B7 (biotin), vitamin B9 (folicacid), and vitamin B12 (various cobalamins; commonly cyanocobalamin invitamin supplements), vitamin C, vitamin D, vitamin E, vitamin K, folicacid and biotin) essential in minute amounts for normal growth andactivity of the body and obtained naturally from plant and animal foodsor synthetically made, pro-vitamins, derivatives, analogs.

In an embodiment, a source of vitamins or minerals can include at leasttwo sources or forms of a particular nutrient. This represents a mixtureof vitamin and mineral sources as found in a mixed diet, and may includenatural forms. Also, a mixture may also be protective in case anindividual has difficulty absorbing a specific form, a mixture mayincrease uptake through use of different transporters, or may offer aspecific health benefit. As an example, there are several forms ofvitamin E, with the most commonly consumed and researched beingtocopherols (alpha, beta, gamma, delta) and less commonly tocotrienols(alpha, beta, gamma, delta), which all vary in biological activity.There is a structural difference such that the tocotrienols can morefreely move around the cell membrane; several studies report varioushealth benefits related to cholesterol levels, immune health, andreduced risk of cancer development. A mixture of tocopherols andtocotrienols would cover the range of biological activity.

The source of selenium can be of inorganic (e.g., selenite, selenate) ororganic in origin (e.g., selenomethionine, selenocysteine, seelnoyeast),all occurring in a habitual mixed diet. Inorganic and organic havedistinct, complementary uptake and distribution mechanisms in the body,thus allowing to optimize selenium provision to the body.

As used herein, “whole food,” “whole food component,” “real food” or“real food component” is understood to mean a food typically ingested byan individual in a normal daily diet when the food is in its natural orprepared state as opposed to any reduced components of the food. Forexample, a whole food may include any known fruits, vegetables, grain,meats or sources of protein, carbohydrate or fat. The “whole food,”“whole food component,” “real food” or “real food component” may beprocessed so they can be used in a tube feed. In an embodiment, thisprocessing is minimal to keep it as close to the “unprocessed” food aspossible, and still be usable in the tube feed. The skilled artisan willappreciate that the use of a “whole food,” “whole food component,” “realfood” or “real food component” does not limit the use of other nutrientsources. For example, powdered fruits and vegetables may also beincluded in the compositions.

As used herein, “zoo-chemicals” refers to functional foods that havehealth benefits beyond basic nutrition, and are health promotingcompounds that are found in animal sources.

Patients that are either inactive or fed one single formula diet for asignificant amount of time are susceptible to metabolic disturbancesthat may result from a lack of variety or proper nutrient values intheir diets. For example, long-term tube-fed patients may suffer fromsuch disturbances. Although the basic nutritional needs of the patientmay be met through tube feeding, current formulas for tube feeding arenot optimized for maintenance of patient health over long time periods.

Patients who receive long-term tube feeds often remain on a singledietary source for weeks, months, or even years. Therefore, thelong-term tube feeding formula must deliver not only the essentialmacro- and micronutrients, but other dietary constituents that maybecome conditionally essential or important for well-being. A short-termtube feeding patient would consume an oral diet before and after thetube feeding episode, thus limiting any negative effects caused by anymissing conditionally essential compounds. Long-term, tube fed patients(often sedentary or bedridden), however, may suffer from any number ofhealth complications for example, increased bone or muscle loss,low-grade inflammation, reduced gastrointestinal motility, increaseresistance and depressed or altered immune systems. The nutritionalneeds of such long-term, tube fed patients with these types of chronicdiseases will certainly differ from those requiring short-term tubefeedings. Accordingly, Applicant has found that patients suffering fromthese processes associated with decreased activity, should beadministered tube feed formulations having adequate calcium, vitamin D,and protein, complex carbohydrates, fiber (including prebiotics),nucleotides, ω-3 fatty acids, antioxidants, phytonutrients, and/orvarious herbs, spices and flavorings, or combinations thereof. Althoughthe feeding needs of long-term tube feed patients is different thanshort-term tube feed patients, the skilled artisan will appreciate thatthe present compositions may be used for either short or long-term tubefeed patients, as well as patients receiving supplemental nutritional.

Many patients on long-term tube feed formulations are older adults.Although the aging process is natural, there are a number ofphysiological changes that should be limited or slowed if possible.These physiological changes include, for example, sarcopenia (loss oflean body mass), increase risk of osteoporosis or fracture, depressedgut health, altered immune function, increase oxidative stress,increased insulin resistance and loss of appetite. Particularly in olderadults, dysphagia, stroke head and neck cancer, and neurological casesincluding, but not limited to, Parkinson's Disease, Alzheimer's andother neurological changes associated with aging are common conditionsthat require tube feeding.

There are many similarities between elderly adult and sedentary adultpopulations. The nutritional compositions that are fed to these patientsshould address, among other conditions, musculoskeletal health, guthealth, immune function, low grade inflammation, oxidative stress andinsulin resistance. Applicant has identified several key nutrients toaddress the needs of adult patients who experience any or all of thephysiological impacts listed above.

For example, adult patients experiencing a change in glucose metabolism,which includes, for example, insulin resistance and impaired glucoseuptake, may be fed nutritional compositions that include ingredientssuch as, but not limited to, complex carbohydrates, fiber, herbs,spices, phytochemicals and/or flavorings such as ginseng or cinnamon.Likewise, adult patients experiencing a change in gut function may befed nutritional compositions that include ingredients such as, but notlimited to, fiber (both soluble and insoluble), prunes, nucleotides,prebiotics and probiotics.

Further, for adult patients experiencing hypercholesterolemia orhypertriglyceridemia or for prevention of related diseases, tube feedformulations or oral nutritional supplements (liquid or solid) mayinclude, for example, ω-3 polyunsaturated fatty acids, monounsaturatedfatty acids, phytochemicals, plant sterols/stanols, soluble fiber, andherbs, spices and/or flavorings including, for example, garlic orcinnamon. The saturated fatty acids, however, should be limited to lessthan 7% of the total energy, the cholesterol should be limited to lessthan 200 mg, and the trans fatty acids should also be limited.

Nutritional compositions including, for example, antioxidants,nucleotides, prebiotics and ω-3 polyunsaturated fatty acids may be fedto adult patients experiencing a decrease in immune function or anincrease in oxidative stress.

Additionally, adult patients experiencing an impact on musculoskeletalhealth including, for example, bone health and muscle mass/strength, maybe fed nutritional compositions having calcium, high amounts of vitaminD and high quality protein. A large bolus of protein may be administeredat a given time to optimize protein synthesis in elderly individuals.See, Arnal M A, et al., Protein pulse feeding improves protein retentionin elderly women, Am. J. Clin. Nutr., 69:1202-8 (1999); see also, Symonset al., Aging does not impair the anabolic response to a protein-richmeal, Am. J. Clin. Nutr., 86:451-6 (2007). Indeed, a bolus of 20-30 gprotein is thought to optimally stimulate protein synthesis. Details ofmany of these conditions are discussed further below with respect to thenutritional needs of pediatric patients. In this way, the skilledartisan will appreciate that many nutrients required by adult patientsmay also be required by pediatric patients.

With respect to children, there are a few basic concepts that apply tomost, if not all, pediatric or young adult patients. For example, thesepatients require adequate and appropriate nutrition to ensure propergrowth. These patients would also benefit from measures to preventchronic diseases. Indeed, preventative nutrition to reduce the risk ofdeveloping coronary vascular disease and cancer later in life may beparticularly relevant for this population.

More specifically, there are conditions common to pediatric patientsthat may require long-term feedings (e.g., tube feedings). Severalconditions include, but are not limited to, cystic fibrosis,quadriplegia, cerebral palsy and neuromuscular disorders. Applicant hasalso identified several key nutrients to address the needs of pediatricpatients who experience any or all of the physiological impacts listedabove.

To ensure adequate growth, pediatric patients must maintain adequatenutritional status (macro- and micronutrients), and be fed nutritionalcompositions that provide adequate energy.

Pediatric patients suffering from poor bone health, which includes, butis not limited to, osteopenia and osteoporosis, may be fed nutritionalcompositions having adequate or high amounts of calcium and vitamin D.

Gut health, including motility and microbiota composition (impacted by avariety of factors, including antibiotic usage), in pediatric patientsmay be improved by providing fiber (insoluble and soluble), prebioticfibers and probiotics, and nucleotides.

Nutritional compositions having increased amounts of fat (e.g., 35-40%total energy), protein, and vitamins and minerals may be fed to patientssuffering from pancreatic insufficiency and/or malabsorption of fat andfat soluble vitamins. Often times, a low-fat diet is recommended inpatients with pancreatic insufficiency to reduce steatorrhea. Patientssuffering from inflammation may be fed nutritional compositionsincluding antioxidants, nucleotides, prebiotics and ω-3 polyunsaturatedfatty acids.

In a more specific example, cerebral palsy is a chronic, non-progressivemotor disability that results from an injury to the developing brainearly in life. Cerebral palsy is generally characterized by dysfunctionsin motor coordination and muscle tone. Because long-term tube fedpediatric patients are often wheel-chair bound or have severe difficultywith ambulation, their energy needs are significantly lower than thoseof healthy children, but their protein needs are often higher.Additionally, as described below, maintenance of bone health, preventionof pressure ulcers and maintenance of healthy immune function, guthealth are common concerns. These children often require exclusive tubefeeding.

Indeed, bone fractures are a significant problem in children withspastic quadriplegia due to many factors. Many children with cerebralpalsy are taking anticonvulsant medications for seizure control, andalterations in vitamin D and calcium metabolism are associated with someanticonvulsant use. See, Hahn, T. J. et al., Effect of ChronicAnticonvulsant Therapy on Serum 25-Hydroxycalciferol Levels in Adults,The New England J. of Med., pp. 900-904 (1972). See also, Hunter, J. etal., Altered Calcium Metabolism in Epileptic Children onAnticonvulsants, British Medical Journal, pp. 202-204 (1971). See also,Hahn, T. J. et al., Phenobarbital-Induced Alterations in Vitamin DMetabolism, J. of Clinical Investigation, Vol. 51, pp 741-748 (1972).Although the influence of anticonvulsant medication on vitamin D statusis not completely clear, it is apparent that non-ambulatory children areat increased risk for bone fractures.

Studies have shown that medications to control seizures, such asphenobarbital and Dilantin, can alter the metabolism and the circulatinghalf-life of vitamin D. Research has also suggested that patients on atleast two anti-seizure medications who are institutionalized and,therefore, not obtaining most of their vitamin D requirement fromexposure to sunlight, increase their vitamin D intake to approximately25 μg (1,000 IU)/day to maintain their serum 25(OH)D levels within themid-normal range of 25 to 45 ng/ml (62.5 to 112.5 nmol/liter). It isthought that this should prevent the osteomalacia and vitamin Ddeficiency associated with anti-seizure medications. Applicant has foundthat pediatric patients suffering from such bone health/anticonvulsantissues may see improvement in these areas if administered nutritionalcompositions having increased amounts of calcium and vitamin D.

In yet another example, patients, and especially children, with cerebralpalsy and neuromuscular disorders are also frequently at risk ofdeveloping pressure ulcers or chronic wounds and, as such, may requirespecial diets. Individuals that are susceptible to chronic woundsinclude, for example, those with prolonged immobilization, bed and chairbound and/or experiencing incontinence, those that are experiencingprotein-energy malnourishment, those with neurological, traumatic orterminal illnesses, or those with circulatory or sensory deficits. See,Agency for Health Care Policy and Research, 1992, 1994. Receivingadequate nutrition plays a key role in prevention and treatment of suchchronic wounds.

For example, specific nutrients including protein, vitamin A, vitamin C,vitamin E, zinc, arginine, citrulline and glutamine can play a role inreducing the risk of developing pressure ulcers, particularly if adeficiency is suspected. Adequate hydration also plays a significantrole in reducing the risk of developing pressure ulcers. Indeed, it hasbeen reported that incidence of pressure ulcer development was lower ina group receiving additional protein, arginine, vitamin C and zinc whencompared to a control group (13% versus 72%). See, Neander, et al., Aspecific nutritional supplement reduces incidence of pressure ulcers inelderly people, Numico Research, www.numico-research.com.

Once a chronic wound or pressure ulcer has developed, various nutrientsplay an important role in healing, with specific nutrients having animpact at different phases of the process. For example, Table 1 belowdemonstrates the key nutrients that impact different phases of woundhealing. As is shown in Table 1, certain vitamins, minerals and aminoacids should be present at the different phases of wound healing.

TABLE 1 Phase Process Key Nutrients Phase I: Wound exudation Vitamin CInflammation Fibrin clot formation Vitamin E Selenium Arginine CysteineMethionine Phase II: Angiogenesis Vitamin A Proliferation Fibroblastproliferation Vitamin C Collagen synthesis Thiamin Wound matrixformation Pantothenic acid and epithelialization Zinc Manganese PhaseIII: Collagen cross linkage Vitamin A Maturation and Remodeling Woundcontraction Vitamin C Tensile strength Zinc development Copper Manganese

Applicant has surprisingly found that pediatric patients suffering frompressure ulcers may see improvement in these areas if administerednutritional compositions having increase amounts of protein, vitamin A,vitamin C, vitamin E, zinc, arginine, citrulline and glutamine.

There are also significant health economic implications with preventionof pressure ulcer development or progression. For example, the averagehealing times for pressure ulcers are longer at later stages of theulcers, with Stage III and Stage IV ulcers requiring substantiallylonger treatment than Stage II. In a UK cost of illness study, it isclear that there are increased treatment costs with increased severityof pressure ulcers. See, Bennett G, et al., The cost of pressure ulcersin the UK, Age and Ageing, 33: 230-235 (2004). In another study, it wasshown that Stage III and Stage IV pressure ulcers cost substantiallymore to treat than Stage II pressure ulcers. See, Xakellis G C, et al.,The cost of healing pressure ulcers across multiple health caresettings, Adv. Wound Care, 9:18-22 (1996). These significant costs areshown below in Table 2.

TABLE 2 Total Treatment Treatment Cost Cost per Pressure per PressureHospitalization Ulcer Including Ulcer Excluding Cost per Hospital StayHospital Stay Pressure Stage Mean (SD) Mean (SD) Ulcer Stage I $1,119 $443  $676 (n = 37) (4,234) (581) Stage III and IV $10,185  $700  $9,485(n = 8) (27,635)  (831) All ulcers $2731  $489  $2,242 (n = 45)(12,184)  (629)

In another example, central adiposity has been associated with insulinresistance and low grade inflammation, thus is it possible thatprovision of low energy, high protein diets to growing children with lowphysical activity will prevent the insulin resistance thus permittingmore effective insulin activity and thus anabolism. High protein dietshave been shown to modulate secretion of anabolic hormones such asgrowth hormone. See, Clarke, et al., Effect of high proteinfeedsupplements on concentrations of growth hormone (“GH”), insulin-likegrowth factor-I (“IGF-I”) and IGF-binding protein-3 in plasma and on theamounts of GH and messenger RNA for GH in the pituitary glands of adultrams, J. Endocrinol. 138 (3):421-427 (1993). See, also, J. R. Hunt, etal., Dietary protein and calcium interact to influence calciumretention: a controlled feeding study, Am. J. Clin. Nutr. 89(5):1357-1365 (2009). See, also, G. Blanchard, et al., Rapid weight losswith a high-protein low-energy diet allows the recovery of ideal bodycomposition and insulin sensitivity in obese dogs, J. Nutr. 134 (8Suppl):21485-21505 (2004).

These benefits are particularly important during rapid growth as thegrowth hormone axis has been shown to be associated with chronicdiseases later in life. Therefore modulation of the growth hormone axis(including IGF-1) will benefit the clinical outcome of the patient bothin the short term and also in later years. This can lead to significantimprovement in quality of life but also in positive health economicoutcomes. See, J. M. Kerver, et al., Dietary predictors of theinsulin-like growth factor system in adolescent females: results fromthe Dietary Intervention Study in Children (DISC), Am. J. Clin. Nutr. 91(3):643-650 (2010).

In another example, hospitalized, institutionalized, and recoveringpatients may be at an increased risk of metabolic disturbances caused bypoor renal and/or pulmonary function. While the body's blood pH isfairly well maintained over time, primarily through regulation by thekidneys and lungs, dietary intake can significantly influence the body'sacid/base balance. As a result, the acid-base potential of the dietbecomes increasingly important in maintenance of the patient's health,including musculoskeletal and immune health.

Upon ingestion and after metabolism, foods can be categorized as eithermore acidic or more alkaline producing. Correlational human intake datasuggests that diets higher in fruits and vegetables support a netalkaline environment to help maintain metabolic homeostasis. Conversely,acid producing diets have been found to negatively impactmusculoskeletal health. Correction of low-grade metabolic acidosisthrough diet modification may help to preserve skeletal muscle mass andimprove the health of patients with a variety of pathological conditionsincluding, for example, muscle loss.

Because long-term tube fed pediatric patients, for example, lackvariation in their food sources they may be particularly susceptible tothe effects of such acid-forming diets. Although the kidneys areefficient at neutralizing acids, long term exposure to high acid isbelieved to overwhelm the kidneys' capacity to neutralize acid andpotential damage may occur. As a result, alkaline compounds thatinclude, but are not limited to, calcium are used to neutralize thesedietary acids (in the case of muscle, glutamine can act as a buffer).The most readily available source of calcium in the body is bone. Onetheory is that high acid diets may contribute to bone loss as the bodymobilizes stored calcium to buffer metabolic acid. The hypothesis isthat low acid diets may result in benefits that include attenuation ofbone and muscle loss as well as maintaining renal health. See, Wachman,A., et al., Diet and Osteoporosis, Lancet, 1:958-959 (1968); see also,Frassetto L, et al., Potassium Bicarbonate Reduces Urinary NitrogenExcretion in Postmenopausal Women, J. Clin. Endocrinol. Metab.,82:254-259 (1997).

In addition to bone specific effects, human correlational data suggeststhat dietary intake of fruits and vegetables support a net alkalineenvironment which can help regulate metabolic homeostatis. This netalkaline state has been associated with an enhanced preservation of leanbody mass, at least in older individuals. See, Dawson-Hughes B, et al.,Alkaline diets favor lean tissue mass in older adults, Am. J. Clin.Nutr., March; 87(3):662-5 (2008). Thus, the manipulation of Phosphorus(P), Sodium (Na), Magnesium (Mg), Potassium (K) and Calcium (Ca) incomplete nutritional formulas can serve to enhance net alkalineproduction to further minimize endogenous skeletal muscle proteolysis aswell as preserve lean body mass. The same is true of the manipulation ofa protein source.

In an embodiment, the nutritional compositions of the present disclosuremay be administered as a bolus or a continuous tube feeding. In anembodiment, the tube feedings are administered as a bolus since itmaximizes the physiological response to the feeding occasion. Thismethod provides complete nutrition to patients in that a concentrateddose of protein is delivered at each feeding. This concentratedprovision of protein is essential to increasing plasma amino acids(e.g., leucine), stimulating protein synthesis, and attaining a netpositive protein balance. This anabolic state post-feeding is requiredto optimize growth though the accrual of lean body mass and linear bonegrowth (accrual of bone mineral density). The mechanism is related tothe above mentioned increase in serum leucine as well as anabolicendocrine response including the stimulation of the insulin-IGF-1-GHaxis leading to increased uptake and bio-utilization of substrates formusculoskeletal development (thus, leading to reduced accumulation ofvisceral adiposity).

The present disclosure is directed to nutritional products andcompositions that provide patients requiring tube feedings and/or oralnutritional supplements with sufficient levels of certain micronutrientsand macronutrients and that mimic a healthy, whole food diet and providephysiological benefits and emotional appeal. In order to mimic a “wholefood” diet, the formulas of the present disclosure may, for example,increase the number and variety of fruits and vegetables, increase thevariety of macronutrient sources and include other components found inwhole foods including, for example, nucleotides, phytonutrients, herbs,spices or flavorings, plant sterols, etc.

One manner in which tube feeding formulas can mimic healthy, whole fooddiets is to increase the servings of fruits and vegetables administeredper day. Indeed, any incremental increase in fruit and vegetable contentas compared to current market tube feed formulations would be beneficialto a tube fed patient or patient requiring oral nutritional supplements.From a review of 200 epidemiological studies, increase intakes of fruitsand vegetables reduced the risk of several types of cancers. See, Blocket al., Fruit, vegetables and cancer prevention: A review of theepidemiological evidence, Nutrition and Cancer, 18: 1-29 (1992).Further, for every one serving per day increase in fruits or vegetables,there was a 4% reduction in coronary heart disease risk. See, Joshipuraet al., The effect of fruit and vegetable intake on risk for coronaryheart disease, Ann. Intern. Med. 134:1106-1114 (2001). In addition,other studies have shown benefits of flavonoid consumption and reducedrisk of death from coronary heart disease. The major sources offlavonoids included teas, apples, and onions. See, Hertog et al.,Dietary antioxidant flavonoids and risk of coronary heart disease: theZutphen Elderly Study, The Lancet, vol. 342, Issue 8878:1007-1011(1993).

Applicant has found that providing at least 5 servings or at least 400 gof fruits and vegetables per complete feeding provides the tube fedpatient with amounts of fruits and vegetables typically recommended toindividuals consuming an oral, whole food diet. In an embodiment, atleast 6 or 7 servings of fruits and vegetables are provided in thepresent nutritional compositions. In yet another embodiment, at least 8servings of fruits and vegetables are provided in the presentnutritional compositions. In an embodiment, the fruits and vegetablereduce the risk of several chronic diseases.

As such, in an embodiment, nutritional compositions of the presentdisclosure include a whole food, or a real food, component. Whole foodscontain beneficial food constituents in addition to the well-recognizedmacronutrients, vitamins and minerals. Several of these foodconstituents include phytochemicals and nucleotides, which provideseveral benefits to a patient on a long-term tube feeding diet, orrequiring oral nutritional supplements, as will be further discussedbelow.

For example, phytonutrients can act as antioxidants within the body.See, Carlson et al., The total antioxidant content of more than 3100foods, beverages, spices, herbs and supplements used worldwide, Nutr.J., 9:3 (2010). Thus, it is beneficial to provide phytonutrients incertain amounts. For example, in a 2008 report, it was estimated that ifan individual consumed 5 servings of fruits and/or vegetables daily,polyphenol intake would be greater than 500 mg, and probably closer to500-1,000 mg if cocoa, tea or coffee is consumed. See, Williamson, etal., Dietary reference intake (DRI) value for dietary polyphenols: arewe headed in the right direction?, British Journal of Nutrition, 99,Suppl. 3, S55-59 (2008).

In a study including Finnish adults (n=2007), mean total intake ofpolyphenols (phenolic acids, anthocyanidins, and other flavonoids,proanthocyanidins, and ellagitannins) was 863±415 mg/d; intakes ofspecific classes included 641 mg/d phenolic acids, 128 mg/d totalproanthocyanidins, 47 mg/d anthocyanidins, 33 mg/d total flavonoids, 12mg/d ellagitannins, 309 mg/d isoflavones, 0.9 mg/d lignans, 5.9 mg/dcarotenoids, and 368 mg/d sterols. The largest contributors to phenolicacid intake was coffee followed by breads and tea; berries and berryproducts to anthocyanins; fruits and tea to flavonols, flavonones andflavones; apples, berries, tea and chocolate to proanthocyanidins;vegetables to carotenoids; soy products to isoflavonoids; and seeds, soyproducts, rye and cereal products to lignans. See, Ovaskainen et al.,Dietary Intake and Major Food Sources of Polyphenols in Finnish Adults,American Society for Nutrition J. Nutr. 138:562-566 (March 2008). Thisinformation is, however, an example and is not necessarilyrepresentative of worldwide intake as it may vary depending on foodpatterns and preferences. In a another study near Indianapolis involving280 people, average intakes of lutein and zeaxanthin, and β-carotene,were 1101±838 and 2935±2698 μg/d, respectively. See, Curran-Celentano etal., Relation between dietary intake, serum concentrations, and retinalconcentrations of lutein and zeaxanthin in adults in a Midwestpopulation, American Journal of Clinical Nutrition, Vol. 74, No. 6,796-802 (December 2001).

It is possible to estimate phytonutrient content to foods by using theUSDA Standard Reference database (Release 23). This database contains,for example, data on carotenoid content in foods. Examples of suchcarotenoid contents include: (i) 1 cup chopped, raw carrots (NDB No:11124), beta carotene 10605 mcg, alpha carotene 4451 mcg, lycopene 1mcg, lutein+zeaxanthin 328 mcg; (ii) 1 cup spinach (NDB No: 11457): betacarotene 1688 mcg, lutein+zeaxanthin 3659 mcg; (iii) 1 cup tomatoes,red, ripe, cooked (NDB No: 11530): beta carotene 703 mcg, lycopene 7298mcg, lutein+zeaxanthin 226 mcg; (iv) 1 cup chopped broccoli, raw (NDBNo: 11090): beta carotene 329 mcg, alpha carotene 23 mcg, betacryptoxanthin 1 mcg, lutein+zeaxanthin 1277 mcg; (v) 1 cup broccoli,frozen, chopped, cooked, boiled, drained, without salt (NDB No: 11093):beta carotene 1098 mcg, alpha carotene 35 mcg, beta cryptoxanthin 2 mcg,lutein+zeaxanthin 2015 mcg; (vi) 1 cup blueberries, raw (NDB No: 09050):beta carotene 47 mcg, lutein+zeaxanthin 118 mcg; (vii) 1 cup halves,strawberries, raw (NDB No: 09316): beta carotene 11 mcg,lutein+zeaxanthin 40 mcg; and (viii) 1 cup slices apple, raw with skin(NDB No: 09003) beta carotene 29 mcg, beta cryptoxanthin 12 mcglutein+zeaxanthin 32 mcg.

The phytonutrient content of foods, however, may vary depending onprocessing, growing conditions, cultivar, etc. See, Kim H J et al.,Changes in Phytonutrient Stability and Food Functionality during Cookingand Processing, Korean J Food Cookery Sci., Vol 22 No 3: 402-417 (2006).Since processing and handling can influence the phytonutrient content ofthe final product, the present disclosure relates to a tube feed thatcontains fruit and vegetable ingredients with known/standardized levelsof select phytonutrients, and are processed in such a manner to maintaina desired level of phytonutrients in the end product.

There are many factors that may impact the phytonutrient content ofvarious fruits and vegetables. For example, physical factors mayinclude, but are not limited to, temperature, pressure,oxidation/reduction potential, pH, enzymes, metals, leaching, light,water activity, etc. Biological factors affecting food constituents mayinclude, but are not limited to, maturity, cultivar, state of thetissue, composition, etc. See, Kalk, Effects of Production andProcessing Factors on Major Fruit and Vegetable Antioxidants, Journal ofFood Science, Vol 70, Nr 1 (2005); see, also, Kim H J, et al., Changesin Phytonutrient Stability and Food Functionality during Cooking andProcessing, Korean J Food Cookery Sci., Vol 22 No 3: 402-417 (2006).Depending on the phytonutrient/fruit or vegetable, processing maydestroy or enhance presence and/or bioavailability. Additionally, Kalkreports that carotenoids are relatively stable through processing, whilephenolic antioxidants are more prone to losses. See, Kalk, Table 3.

Furthermore, the impact of processing on tomatoes phytonutrient levelshas been well studied, such that thermal processing increases thebioavailable content of lycopene. See, Dewanto et al., ThermalProcessing Enhances the Nutritional Value of Tomatoes by IncreasingTotal Antioxidant Activity, J. Agric. Food Chem., 50 (10), pp 3010-3014(2002). On the other hand, thermal processing of other fruits andvegetables may degrade these components. Severe heat treatment of redcabbage (e.g., canning) resulted in 73% degradation of glucosinolates.See, Oerlemans et al., Thermal degradation of glucosinolates in redcabbage, Food Chemistry, 95; 19-29 (2006). Similar results were foundduring cooking of broccoli (74% loss after microwaving). See, Vallejo,F. et al., Glucosinolates and vitamin C content in edible parts ofBroccoli florets after domestic cooking, European Food Research andTechnology, 215, 310-316 (2002).

Another manner in which nutritional compositions can mimic healthy,whole food diets is to increase the variety of food consumed per day.For example, with respect to macronutrients, it is important thatnutritional compositions include a variety protein, fat and carbohydratesources. Indeed, formulations having a variety of protein, fat andcarbohydrate sources more closely resemble a whole food diet. Withrespect to micronutrients, the source of vitamins and minerals includesat least two sources or forms of a particular nutrient.

The present nutritional compositions may include at least 4 differentsources of macronutrients, which include, for example, protein, fat, andcarbohydrates. In another embodiment there may be at least 5, 6, 7, or 8different sources of macronutrients. In an embodiment, there exists atleast one source each of protein, fat and carbohydrates in thenutritional compositions. However, the skilled artisan will appreciatethat there may be any combination of the at least 8 different sources ofmacronutrients. For example, there may be 3 or more protein sources inthe present nutritional compositions. In an embodiment, there may be 3or more carbohydrate sources in the nutritional compositions. In anotherembodiment, there may be at least 3 or more fat sources in thenutritional compositions. Alternatively there may be 4 or more of theprotein, carbohydrate, fat or fiber sources in the composition. Thesources may be the same source, or a different source. In anotherembodiment, there may be at least 3 or more fiber sources in thenutritional compositions.

In an embodiment, vegetable proteins may be included to further enhancethe net alkaline profile of the formula while delivering high qualityprotein blends that provide the essential nutritional requirements forsupporting growth and development. Based on the nutritional profile ofspecific vegetable proteins (e.g., pea protein isolate) there arelimitations in the amount of vegetable protein sources that can beincluded in a formula. For example, the amino acid profile of peaprotein includes all of the indispensable amino acids. Pea protein isrelatively rich in arginine, but limiting in the sulphur-containingamino acids, methionine, and cysteine. However, it is possible, forexample, to blend pea protein isolates with a complete protein source(such as milk protein or complete vegetable proteins) having sufficientsulphur-containing amino acids to offset such deficiency. Canola protein(i.e., isolates, hydrosylates and concentrates) is one such vegetableprotein which can provide appreciable amounts of sulfur-containing aminoacids to further augment the amino acid profile to deliver the necessaryprotein quality to the patient. Additionally, animal derived proteinsare typically more abundant in sulphur-containing amino acids thanvegetable proteins. Furthermore, given the potential for viscositylimitations associated with, for example, tube feeding and the need tomaintain the necessary nutritional value of protein, the formula mayinclude about 10-50% protein coming from a vegetable source.

The present compositions may also use a mixture of macronutrient sourcesthat have associated health benefits and/or emotional appeal. Forexample, the protein may be derived from vegetable sources whilemaintaining high Protein Digestibility Corrected Amino Acid Scores(“PDCAAS”). The fat sources may include olive and canola oil, and may beless refined to maintain higher polyphenol content.

The skilled artisan will appreciate that the protein content of thepresent nutritional compositions may be higher than typical long-termtube feed formulations in embodiments having high amounts of protein.For example, the Recommended Dietary Allowance (“RDA”) of protein forboth men and women is 0.80 g of good quality protein/kg body weight/dayand is based on careful analysis of available nitrogen balance studies.See, National Academy of Sciences, Institute of Medicine, Food andNutrition Board, Dietary Reference Intakes for Energy, Carbohydrate,Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids(Macronutrients), Chapter 10 (2005). In an embodiment, the presentcompositions provide protein to a patient in an amount of from about 1.0to 2.5 g/kg body weight/day. In another embodiment, the presentcompositions provide protein to a patient in an amount of about 1.5 to2.0 g/kg body weight/day. Accordingly, the present compositions mayprovide protein to a patient in an amount that is nearly twice the RDAof protein for men and women.

In another embodiment, the protein is provided in an amount to provideabout 5 to about 40% energy from protein per day. In another embodiment,the protein is provided in an amount to provide from about 10% to about35% energy from protein per day. In another embodiment, the protein isprovided in an amount to provide from about 25% to about 30% energy fromprotein per day.

Sources of complex carbohydrates or whole grains such as, for example,bran, oatmeal, barley, beans, rice, and peas, may be used in the presentcompositions, as recommended in the Dietary Guidelines of the DietaryGuidelines Advisory Committee. Any suitable carbohydrate may be used inthe present nutritional compositions including, but not limited to,sucrose, lactose, glucose, fructose, corn syrup solids, maltodextrin,modified starch, amylose starch, tapioca starch, corn starch orcombinations thereof. Carbohydrates may be provided in an amountsufficient to provide from about 40% to about 70% total energy. In anembodiment, the carbohydrates are provided in an amount sufficient toprovide from about 45% to about 65% total energy of the nutritionalcompositions.

A source of fat may also be included in the present nutritionalcompositions. The source of fat may include any suitable fat or fatmixture. For example, the fat source may include, but is not limited to,vegetable fat (such as olive oil, corn oil, sunflower oil, rapeseed oil,hazelnut oil, soy oil, palm oil, coconut oil, canola oil, lecithins, andthe like), animal fats (such as milk fat, tallow, lard, poultry fat,fish oil, etc.), or combinations thereof. Additionally, fats such asolive oil and canola oil may be used in the present compositions and arecommonly purported to have heart health benefits. Fats may be providedin an amount sufficient to provide from about 20% to about 40% totalenergy. In an embodiment, the fats are provided in an amount sufficientto provide from about 25% to about 35% total energy of the nutritionalcompositions.

With respect to fruits and vegetables, the present compositions mayincrease the variety of foods consumed per day by combining and usingseveral different types of fruits and vegetables. The nutritionalcompositions of the present disclosure may provide fruits and vegetablesin an amount recommended by individuals consuming a whole food diet. Inone embodiment, the effective amount is at least about 3 servings offruits and vegetables. In an embodiment, the nutritional compositionsinclude from about 4 to about 10 servings of fruits and vegetables. Inan embodiment, the nutritional compositions include at least about 6 or7 servings of fruits and vegetables. In an embodiment, any incrementalamount of fruits and vegetables is beneficial.

Fruits included in the present nutritional compositions may include anyknown fruit such as, but not limited to, apples, bananas, coconut, pear,apricot, peach, nectarines, plum, cherry, blackberry, raspberry,mulberry, strawberry, cranberry, blueberry, grapes, prunes, grapefruit,kiwi, rhubarb, papaya, melon, watermelon, pomegranate, lemon, lime,mandarin, orange, tangerine, guava, mango, pineapple, etc. Similarly,vegetables may include any known vegetable such as, but not limited to,amaranth, arugula, brussels sprouts, cabbage, celery lettuce, radicchio,water cress, spinach, pumpkin, squash, mushrooms, peas, beans, beets,carrots, potatoes, radish, rutabaga, turnips, etc.

It is also possible to include fruits and vegetables from the fivedifferent colors categories, which represent a variety in the types ofphytochemicals provided in the formulation. See, Heber D, et al.,Applying Science to Changing Dietary Patterns, J. Nutr, 131:3078 S-3081S(2001). Phytochemicals are non-nutritive compounds that are found inmany fruits and vegetables, among other foods. There are thousands ofphytochemicals that can be categorized as flavonoids and allied phenolicand polyphenolic compounds, terpenoids, e.g., carotenoids and plantsterols, or alkaloids and sulfur containing compounds.

With respect to the color groups of fruits and vegetables, the presentcompositions may include at least one fruit/vegetable from each of thecolors green, blue/purple, red, orange and white. Greenfruits/vegetables include, for example, spinach, broccoli, peas, beansand kiwi. Blue/purple fruits/vegetables include, for example, grapes,blueberries and eggplant. Red fruits/vegetables include, for example,raspberries, cranberries and tomatoes. Orange fruits/vegetables include,for example, carrots, mangoes, pumpkin, oranges and squash. Whitefruits/vegetables include, for example, cauliflower, onion and banana.Accordingly, it is possible to diversify the nutrient and phytonutrientcontent by including fruits and vegetables from all color groups. Theskilled artisan will appreciate that this list is not exhausted and thatother colored fruits/vegetables may be used in addition to those listedabove. The skilled artisan will appreciate that any known fruits andvegetables may be used in the present nutritional compositions. Further,the skilled artisan will also appreciate that the fruits and/orvegetables may be provided in any amounts effective to achieve theadvantages described above.

Phytochemicals are active in the body and, in general, act similarly toantioxidants. They also appear to play beneficial roles in inflammatoryprocesses, clot formation, asthma, and diabetes. Researchers havetheorized that to receive the most benefit from consumption ofphytochemicals, they should be consumed as part of whole foods, becauseof the complex, natural combination and potentially synergistic effects.See, Liu R H., Health benefits of fruit and vegetables are from additiveand synergistic combinations of phytochemicals, Am. J. Clin. Nutr.,78:517 S-520S (2003). This may partially explain the health benefitsassociated with consumption of whole fruits and vegetables. Increasedintake of fruits and vegetables is associated with reduced risk of manychronic diseases. In order to enhance the phytochemical profile of thepresent nutritional compositions, in an embodiment, the compositionsinclude various fruits and vegetables containing these compounds.

Another manner in which tube feeding formulas can mimic healthy, wholefood diets is to include food components that are typically present in ahealthy, whole food diet. To this end, the present compositions may haveadded spices, herbs or flavorings with purposed health benefits such as,for example, antioxidant activity, or that provide emotional appeal forcertain populations. For example, the present compositions may includegarlic and/or cinnamon to reduce cholesterol and lower blood pressure,ginseng and cinnamon for glycemic control, tumeric, curcumin, basil,rosemary, mint and lemon grass for anti-carcinogenic properties, gingerfor arthritic pain, ginkgo biloba and ginseng for cognitive function,curcumin and ginger for anti-inflammatory properties, ginger for ananti-nausea, and herbs for improving general health conditions.

Variety in food and tastes may maintain the various taste receptors inthe gut. Increased variety of foods and/or food components and flavorsmay be delivered to stimulate specific taste receptors in the gut, thuseliciting different physiological responses. For example, umamireceptors have been identified in the gastrointestinal tract, whichsense the presence of savory flavors (mushrooms, seafood, fermented soyflavorings, or common flavor enhancers such as monosodium glutamate(“MSG”) and/or inosine-5′-monophosphate (“IMP”)). Animal data has shownthat the addition of MSG and/or IMP to diets improves the secretion ofmucus and protection of the small bowel. In an embodiment, mushrooms andfermented soy flavorings may be added to the present compositionsbecause mushrooms and fermented soy flavorings such as, for example, soysauce, contain the highest naturally occurring levels of these compoundsand could be useful as ingredients in tube feed formulations for supportof the gastrointestinal tract. In this manner, umami receptor activationmay have dual benefits in glucose metabolism (increase GLP-1 release)and in duodenal mucosal protection and regeneration due to GLP-2 releasefrom L cells. See, Nakamura E, et al., Physiological roles of dietaryfree glutamate in gastrointestinal functions, Biol. Pharm. Bull., 31,10:1841-1843 (2008); Kojo A, et al., Effects of glutamate, the “umami”substance, on development and healing of NSAID-induced small intestinallesions in rats, Abstract presented at Digestive Disease Week 2010(W1345); Wang J, et al., Umami receptor activation increases duodenalbicarbonate secretion via GLP-2 release in rats, Abstract presented atDigestive Disease Week 2010 (W1719).

Also, stimulation of other taste receptors has been shown to haveeffects in animal or cell culture studies. For example, stimulation ofbitter taste receptor in the gut increases CCK release and delaysgastric emptying. See, Chen M C, et al., Bitter stimuli induce Ca2signaling and CCK release in enteroendocrine STC-1 cells: role of L-typevoltage-sensitive Ca2 channels, Am. J. Physiol. Cell Physiol. 291,C726-C739 (2006); Jang H J, et al., Gut expressed gustacin and tastereceptors regulate secretion of glucagon-like peptide 1., Proc. Natl.Acad. USA 104:15069-74 (2007); Margolskee R F, et al., T1R3 andgustducin in gut sense sugars to regulate expression of Na-glucosecotransporter 1., Proc. Natl. Acad. USA 104:15075-80 (2007); Mace O J,et al., Sweet taste receptors in rat small intestine stimulate glucose,J. Physiol. 582.1, pp 379-392 (2007).

In an embodiment, the present compositions include plant sterols forheart health to reduce absorption of cholesterol in the gut.Phytosterols (also called plant sterols) are a group of steroid alcoholsthat naturally occur in plants. Phytosterols occur naturally in smallquantities in vegetable oils, especially sea buckthorn oil, corn oil,and soybean oil. One example of a phytosterol complex, isolated fromvegetable oil, is cholestatin, composed of campesterol, stigmasterol,and brassicasterol. The skilled artisan will appreciate that any knownphytosterols may be used herein. In an embodiment, up to about 5 g ofplant sterols may be added to the present compositions per completefeed. In an embodiment, about 1 to about 4 g of plant sterols may beadded to the present compositions. In another embodiment, about 2 g ofplant sterols are added to the present compositions per complete feed.In this manner, plant sterols may be beneficial in compositionscontaining cholesterol, or an oral nutritional supplement in which theconsumer is consuming other food items containing cholesterol. Inanother embodiment, however, some long-term tube-fed patients receivevery little amounts of exogenous cholesterol. In this case, the presentcompositions may not include sterols that may hamper cholesterol.

As discussed above, nucleotides are food constituents found in severaltypes of food including red meats, organ meats, poultry, fish,shellfish, lentils, beans, asparagus and fermented beverages, amongothers. Although endogenous synthesis constitutes a major source ofnucleotides, nucleotides can also be obtained in the form ofnucleoproteins naturally present in all foods of animal and vegetableorigin including, for example, animal protein, peas, yeast, beans andmilk. Further, concentrations of RNA and DNA in foods are dependent oncell density. Thus, meat, fish and seeds have higher nucleotide contentthan milk, eggs and fruits. Consequently, organ meats, fresh seafood,and dried legumes are rich food sources. Endogenous synthesis ofnucleotides, although a high energy requiring process, appears to besufficient in healthy individuals. However, the need for exogenous(dietary source) nucleotides occurs during situations of growth orstress, e.g., gut injury, sepsis, and immune challenge. See, Kulkarni etal., The Role of Dietary Sources of Nucleotides in Immune Function: AReview, J. Nutr., vol. 124 pp. 1442S-1446S (1994). Therefore, severalsegments of the population on long-term tube feeds (elderly, pediatricpopulations, sedentary, bedridden and those with wounds), or patientsrequiring oral nutritional supplements, may particularly benefit fromexogenous nucleotides.

The skilled artisan will appreciate that although endogenous synthesisconstitutes a major source of nucleotides, nucleotides can also beobtained in the form of nucleoproteins naturally present in all foods ofanimal and vegetable origin including, for example, animal proteins,peas, yeast, beans, milk, etc.

The cell energy charge has been proposed as an important control for thecell to favor either anabolic or catabolic processes. Cell energy chargeis defined Energy charge=(ATP+½ ADP)/(ATP+ADP+AMP), where ATP, ADP, andAMP signify adenosine 5′-triphosphate, -diphosphate, and -monophosphate,respectively. Metabolic stress, nutritional stress, or both may resultin a loss of nucleotides from the adenylate pool and becomeconditionally essential under these conditions. The maintenance of thecell energy charge can attenuate the upregulation of catabolic processesresulting from metabolic stress, nutritional stress, or both, whichincludes protein breakdown.

AMP Protein Kinase (“AMPK”) is a protein that serves as a cell energycharge sensor that responds to ATP/AMP as well phosphocreatine/creatine(“PCr”/“Cr”) changing ratios for the prioritization of cellularprocesses based on available energy. Specifically, AMPK can target thetranslational control of skeletal muscle protein synthesis as well asupregulate the ubiquitin proteosome pathway.

Additionally, nucleotides can be beneficial in the nutritionalmanagement of pressure ulcer by improving the resistance to infection atthe wound site. Chronic nucleotide supplementation may counteract thehormonal response associated with physiological stress, resulting in anenhanced immune response.

Extensive experimentation on the influence of dietary nucleotides onlymphocyte function and cellular immunity in rodent models has also beenconducted. Evidence exists to assert that the absence of dietarynucleotides does significantly decrease specific and non-specific immuneresponses. Findings include decreased maturation and proliferation oflymphoid cells in response to mitogens, decreased resistance tobacterial and fungal infection, and increased allograft survival.

Lymphocyte differentiation and proliferation can be stimulated byspecific nucleosides and, in turn, nucleotide metabolism may beinfluenced by stages of lymphocyte activation and function. Furthermore,de novo synthesis and salvage of purines and pyrimidines is increased instimulated lymphocytes. In support, an established marker forundifferentiated T-cells, terminal deoxynucleotidyl transferase (“TdT”),has been identified in undifferentiated bone marrow and thymocytes ofrodents fed diets devoid of nucleotides.

In vitro and in vivo studies of rodents on nucleotide free diets havedemonstrated suppressed cell-mediated immune responses. Spleniclymphocytes from nucleotide free hosts evidenced significant decreasesin proliferate response to mitogens, decreased interleukin-2 (“IL-2”)production and lower levels of IL-2 receptor and Lyt-1 surface markers.IL-2 is a growth factor for lymphocytes, while Lyt-1 is a marker ofhelper-inducer T-cell immunity. Delayed cutaneous hypersensitivity wasalso lower.

These responses were largely reversed with additions of RNA or uracil,suggesting a formidable role for pyrimidines and/or limited capacity fortheir salvage. Furthermore, dietary nucleotides were shown to reverselost immune response secondary to protein-calorie malnutrition more sothan calories and protein alone. However, this reversal was limited topyrimidines.

Investigations of the role of nucleotides in bacterial and fungalinfection have also revealed increased resistance. Rodents on nucleotidecontaining diets demonstrated significant resistance to intravenouschallenge of Staphylococcus aureus compared to those on nucleotide freediets. A decreased ability to phygocytose S. aureus was observed.Moreover, decreased survival times were observed in rodents on anucleotide free diet after similar challenge with Candida albicans.Additions of RNA or uracil, but not adenine were shown to increasesurvival time.

The immunosuppressive effects of nucleotide free diets have alsoproduced prolonged cardiac allograft survival in rodents as well assynergistic immunosuppression with cyclosporine A. These findingsevidence influence on T-helper cell numbers and function. Variousmechanisms of action have been proposed to explain these findings.Restriction of exogenous nucleotides is believed to influence theinitial phase of antigen processing and lymphocyte proliferation viaaction on the T-helper-inducer as evidenced by increased levels of TdTin primary lymphoid organs. This is also suggestive of suppression ofuncommitted T-lymphocyte response. Also, nucleotide restriction maycause arrest of T lymphocytes in the G phase of the cell cycle, thusinhibiting transition of lymphocytes to the S phase to illicit necessaryimmunological signals. Nucleotide restriction may also lower thecytolytic activity of natural killer (“NK”) cells and lower macrophageactivity.

Dietary nucleotides may also modulate T-helper cell mediated antibodyproduction. A review of studies investigating nucleotide actions onhumoral immune response identified effects in in vitro and in vivoanimal models as well as in vitro actions in human systems. In vitrofindings in splenic rodent cells primed with T-cell-dependent antigensdisplayed significant increases in the number of antibody producingcells in yeast RNA containing cultures. RNA additions to normal strainsdemonstrated similar results and were nullified by T-cell depletion.Thus, the antibody did not increase in response to T-cell independentantigens or polyclonal B cell activation. The specific antibody responseof yeast RNA was attributed to nucleotides.

Immunoglobulin production has also been shown to increase in in vitroadult human peripheral blood mononuclear cell in response to T-celldependent antigen and stimuli. Specifically, this involved increasedimmunoglobulin M (“IgM”) and G (“IgG”) production. IgM productionincreased in the functionally immature umbilical cord mononuclear cellsin response to T-cell dependent stimuli as well.

Accordingly, in a state of nucleotide deficiency, incorporated dietarynucleotides could potentially exert similar immune effects in vivo.Antibody response to T-cell dependent antigen was suppressed in rodentsmaintained on nucleotide free diets for prolonged periods, and immunefunction was rapidly restored with nucleotide supplementation. However,the mixture used for supplementation showed no effect on in vitroantibody production to antigen-dependent antigens suggestive ofnucleotide effects on local, specific immune response. In addition,significant increases in the numbers of antigen-specificimmunoglobulin-secreting cells were observed in rodent splenic cells inthe presence of nucleotides. Additions of AMP, GMP or UMP have alsoresulted in increased IgG response in rodents. GMP was also shown toincrease IgM response. Studies in preterm infants on nucleotidesupplemented formulas have revealed increased circulating levels of IgMand IgA in the first three months of life as well as higherconcentrations of specific IgG against α-casein and β-lactoglobulin inthe first month of life. Specific IgG levels to low response antigensmay also increase in normal infants receiving dietary nucleotidecontaining formulas.

Mechanistically, in vitro and in vivo observations are thought toinvolve nucleotide effects on T-helper-cells at antigen presentation,modulations via interactions with cell surface molecules of T-cells,suppressed nonspecific activation of T-cells in response to antigenstimulus, and increased specific antibody response mediated throughresting T-cells. Therefore, dietary nucleotides may favor the balance ofT-cell differentiation to T-helper-2 cells which are primarily involvedin B cell response. Thus, it is clear that nucleotides, as well asphytochemicals, can present several physiological benefits to patientshaving any of the above-mentioned conditions.

The skilled artisan will appreciate that any known fruits and vegetablesmay be used in the present nutritional compositions. Further, theskilled artisan will also appreciate that the fruits and/or vegetablesmay be provided in any amounts effective to provide nutrients to achievethe advantages described above. The skilled artisan will also appreciatethat the major sources of nucleotides include red meats, organ meats,poultry, fish, shellfish, lentils, beans, asparagus, etc. In anembodiment, the nutritional compositions of the present disclosure mayprovide nucleotides in an amount of at least about 10 mg/100 kcal. In anembodiment, the nutritional compositions include from about 13 mg/100kcal to about 19 mg/100 kcal nucleotides. In an embodiment, thenutritional compositions provide about 16 mg/100 kcal nucleotides.

In another embodiment, the nutritional compositions may includepolymeric forms of nucleotides. The nucleotides may be present inamounts from about 0.9 to about 1.5 g/1000 kcal. In an embodiment, thenucleotides may be present in amounts up to about 1.2 g/1000 kcal. Asdiscussed above, the skilled artisan will appreciate that althoughfruits and vegetables may provide an amount of nucleotides, exogenoussynthesis may also constitute a major source of nucleotides.

In an embodiment, the nutritional compositions of the present disclosuremay be hypocaloric (e.g., characterized by a low number of dietarycalories) in order to provide a patient with proper nutrients but tomanage weight gain without compromising musculoskeletal health.Typically, hypocaloric diets usually provide between 1,000 and 1,200kcal/day. The present nutritional compositions may have caloricdensities that range from about 0.3 to about 1.0 kcal/ml. In anembodiment, the nutritional compositions have a caloric density fromabout 0.5 to about 0.8 kcal/ml. The tube feed formula may also be ofaverage to high energy density, from about 1.0 kcal/mL to 2.0 kcal/mL.

Osmolality is a measure of the osmoles of solute per kilogram of solvent(osmol/kg tube feeding or Osm/kg tube feeding). In an embodiment, thepresent nutritional compositions may have an osmolality that is lessthan or equal to 800 mOsm/kg water. In another embodiment, the presentnutritional compositions have an osmolality that is less than or equalto 400 mOsm/kg water. In another embodiment, the present nutritionalcompositions have an osmolality that is less than or equal to 380mOsm/kg water.

In an embodiment, the nutritional compositions further include one ormore prebiotics. Non-limiting examples of prebiotics include acacia gum,alpha glucan, arabinogalactans, beta glucan, dextrans,fructooligosaccharides, fucosyllactose, galactooligosaccharides,galactomannans, gentiooligosaccharides, glucooligosaccharides, guar gum,inulin, isomaltooligosaccharides, lactoneotetraose, lactosucrose,lactulose, levan, maltodextrins, milk oligosaccharides, partiallyhydrolyzed guar gum, pecticoligosaccharides, resistant starches,retrograded starch, sialooligosaccharides, sialyllactose,soyoligosaccharides, sugar alcohols, xylooligosaccharides, theirhydrolysates, or combinations thereof.

The nutritional compositions may further include one or more probiotics.Non-limiting examples of probiotics include Aerococcus, Aspergillus,Bacteroides, Bifidobacterium, Candida, Clostridium, Debaromyces,Enterococcus, Fusobacterium, Lactobacillus, Lactococcus, Leuconostoc,Melissococcus, Micrococcus, Mucor, Oenococcus, Pediococcus, Penicillium,Peptostrepococcus, Pichia, Propionibacterium, Pseudocatenulatum,Rhizopus, Saccharomyces, Staphylococcus, Streptococcus, Torulopsis,Weissella, or combinations thereof.

One or more amino acids may also be present in the nutritionalcompositions. Non-limiting examples of amino acids include alanine,arginine, asparagine, aspartate, citrulline, cysteine, glutamate,glutamine, glycine, histidine, hydroxyproline, hydroxyserine,hydroxytyrosine, hydroxylysine, isoleucine, leucine, lysine, methionine,phenylalanine, proline, serine, taurine, threonine, tryptophan,tyrosine, valine, or combinations thereof.

The nutritional compositions may further include one or more synbiotics.Examples may include, for example, bifidobacteria andfructo-oligosaccharides (“FOS”); Lactobacillus rhamnosus GG and inulins;bifidobacteria or lactobacilli with FOS; or inulins orgalactooligosaccharides (“GOS”).

One or more antioxidants may also be present in the nutritionalcompositions. Non-limiting examples of ingredients with antioxidantactivities selected from the group consisting of herbs, spices, andflavorings, carotenoids, flavonoids, polyphenols, lignan, lutein,lycopene, quercetin, limonin, coenzyme Q10 (“CoQ10”), glutathione, Goji(wolfberry), lactowolfberry, hesperidine, selenium, vitamin A, vitaminC, vitamin E, or combinations thereof. In an embodiment, the herbs,spices, and flavorings may be selected from the group consisting ofgarlic, cinnamon, ginseng, turmeric, curcumin, rosemary, mint,lemongrass, ginkgo, ginger, or combinations thereof.

The nutritional compositions also include fiber or a blend of differenttypes of fiber. The fiber blend may contain a mixture of soluble andinsoluble fibers. Soluble fibers may include, for example,fructooligosaccharides, acacia gum, inulin, etc. Insoluble fibers mayinclude, for example, pea outer fiber.

As discussed above, the present compositions may also include a varietyof herbs, spices and/or flavorings. Herbs that are included may beselected from angelica, bay laurel, chives, dill, catnip, fennel,lavender, lemon balm, majoram, mint, oregano, parsley, rosemary, rue,sage, tarragon, thyme, verbena, or combinations thereof. Spices may beselected from the group consisting of black pepper, cumin, cardamom,cayenne, celery seeds, chili pepper, cinnamon, clove, cumin, garlic,ginger, mustard, nutmeg, onion, paprika, peppercorns, tabasco, tumericor combinations thereof. Flavorings may be any natural or artificialflavors or flavor enhancers such as, for example, MSG, vanilla extract,etc. The skilled artisan will appreciate that many herbs, spices andflavorings may overlap in uses such that, for example, a typical herbmay be used as a spice.

The present compositions may further include a source of ω-3polyunsaturated fatty acids including, but not limited to, α-linolenicacid (“ALA”), eicosatetraenoic acid (“ETA”), eicosapentaenoic acid(“EPA”), docosapentaenoic acid (“DPA”), docosahexaenoic acid (“DHA”),tetracosapentaenoic acid, tetracosahexaenoic acid (nisinic acid), orcombinations thereof. Sources of ω-3 fatty acids include fish oil,poultry, eggs, or other plant or nut sources such as flax seed, walnuts,almonds, algae, krill, modified plants, or combinations thereof. Thepresent compositions may also include conjugated linoleic acid (“CLA”).CLA is a naturally occurring lipid that supports lean body mass andimmune function. Grass-fed beef is a good source of CLA.

The present compositions may also include monounsaturated fatty acidsincluding, for example, palmitoleic acid, cis-vaccenic acid, and oleicacid. Common sources of monounsaturated fatty acids include, but are notlimited to, natural foods such as nuts and avocados, and monounsaturatedfatty acids are the main component of tea seed oil and olive oil (oleicacid). Canola oil is 57%-60% monounsaturated fat, olive oil is about 75%monounsaturated fat while tea seed oil is commonly over 80%monounsaturated fat. Other sources of monounsaturated fatty acidsinclude macadamia nut oil, grapeseed oil, groundnut oil (peanut oil),sesame oil, corn oil, whole grain wheat, oatmeal, safflower oil,sunflower oil, tea-oil, and avocado oil.

As discussed above, the present disclosure also provides compositionsand method that provide an emotional appeal for tube fed patients and/ortheir caretakers, as well as possible physiological benefits to thepatient. In order to provide such an emotional appeal, the formulas ofthe present disclosure may, for example, 1) incorporate organic, naturaland sustainable ingredients, 2) provide formulations that are specificto a certain ethnicity, use natural ingredients to provide coloring, 3)provide pediatric-friendly food blends and/or packaging that a parentwould consider “normal” for children consuming an oral diet, 4) providea component that allows for oral stimulation and a natural response toeating, and/or 5) provide methods of tube feeding that mimic typicalmeal times or a cycling menu.

One manner in which a nutritional composition (e.g., a tube feedformulation) may evoke an emotional appeal (and/or potentialphysiological benefit) is to provide organic, natural and sustainableingredients. For example, compositions of the present disclosure mayinclude 100% organic fruits and/or vegetables and organic meat productssuch as chicken or beef. To be certified organic, ingredients must begrown and manufactured according to country-specific standards. TheUnited States Department of Agriculture (“USDA”) Organic CertifiedFruits and vegetables or Meat provides that fruits and vegetables mustbe grown without synthetic or non-organic pesticides, insecticides orherbicides.

For organic meat, the USDA provides that meat must be grown without theuse of antibiotics and growth hormones. Organic products are typicallyfree of artificial food additives, and are processed with fewerartificial methods such as chemical ripening, food irradiation,genetically modified organisms, etc. In an embodiment, the compositionsof the present disclosure may include meat that is obtained from freerange chicken and/or grass-fed beef and milk. Standards such as these,although not necessary, are more aligned with the current marketingmessage of “the way nature intended.” Indeed, it is known that a cow'srumen is not intended to process grains, and these standards assure thatthe meat is raised without the use of antibiotics and growth hormones.See, Steve Windley, Grass-fed Beef, purehealthMD.com (2008).

Similarly, all natural ingredients may be used in the coloring ofpresent compositions to avoid the chemicals in artificial coloring. Forexample, to achieve a composition with red color, amaranth, beets, orhibiscus may be added to the compositions. Alternatively, to achieve acomposition with yellow/orange color, tumeric may be added to thecompositions. The skilled artisan will appreciate that these are merelyexamples of color-providing fruits/vegetables and that any known fruitsor vegetables capable of providing color to the compositions may beused.

Another manner in which a nutritional composition may evoke an emotionalappeal (and/or potential physiological benefit) is to create ethnicityspecific tube feed formulas. In an embodiment, the present compositionsare formulated with fruits, vegetables, macronutrient sources and spicestypically consumed in specific regions of the world. For example, a tubefeed formulation may include curcumin or tumeric and be marketed as anIndian cuisine formulation. Curcumin is a component of the spice tumeric(curcuma longa) and is responsible for the yellow color of curry.Curcumin has specifically been shown to possess anti-inflammatory,antioxidant and anti-proteolytic properties. With regards to long-term,tube fed pediatric patients who experience profound decrements in leanbody mass, for example, curcumin may provide some attenuation ofskeletal muscle proteolysis. Importantly, curcumin has been shown toantagonize the upregulation of nuclear factor-Kβ (NF-Kβ) and this geneis inextricably tied to initiating an intracellular signaling cascaderesponsible for inducing skeletal muscle atrophy during unloadingconditions. See, Farid, et al., Effects of dietary curcumin orN-acetylcysteine on NF-κB activity and contractile performance inambulatory and unloaded murine soleus, J. Clin. Invest., 114(10):1504-11(2005).

Similarly, cumin, oregano and chili powder may be included incompositions that are marketed as a Mexican cuisine formulation. Othercuisine options include, but are not limited to, That, Italian,Mediterranean, or American.

Another manner in which a nutritional composition may evoke an emotionalappeal is to include pediatric-friendly food blends, or foods thatparents would consider “normal” for kids consuming an oral diet. Popularbranded foods include, for example, Cheerios®, Juicy Juice®, Campbell'sAlphabet Soup™, chicken nuggets, strawberry shortcake, bananas, applesauce, etc.

Yet another manner in which a nutritional composition may evoke anemotional appeal (and/or potential physiological benefit) is to providean extra, add-on component that has at least one characteristic selectedfrom the group consisting of visually appealing/appetizing, an appealingaroma, an appealing flavor or smell to stimulate the natural response toeating, or combinations thereof. These components (smell, taste,thought, etc.) may also have physiological benefits such that theyelicit the cephalic phase or the first part of digestion, which wouldallow the patient begin the digestive processes in a more similar way toan oral diet. Therefore, digestive processes begin with the sight, smellor thought of food and physiological processes occur to prime the bodyfor digestion (e.g., salivation, gastric acid secretion, pancreaticendocrine and exocrine).

The add-on component may be a tablet, lozenge, dissolvable strip, orchewing gum. It may or may not be nutritive or contain calories. Ifintended for a strictly Nothing Per Orem (“NPO”) patient, the add-oncomponent could be tailored to ensure compliance (e.g., providedissolvable strip form).

The aroma may be any aroma known in the art. For example, the aroma maybe a dessert aroma such as, but not limited to vanilla, chocolate,strawberry, lemon, custard, etc. The aroma may also be related to anethnic food such as, for example, curry, chili powder, roasted redpepper, basil, etc. In another embodiment, the aroma may be an aromathat is associated with common American foods such as, but not limitedto, meatloaf, chicken, roast, mashed potatoes, etc. By providing a widerange of aromas, the patients may be able to select an aroma that soundssatisfying to the patient at the time of tube feeding. The aroma may bereleased upon opening the packaging, or the smell may be enhanced by a“scratch-and-sniff” device.

The packaging of the tube feeding formula, for example, and add-ondevice can be designed to mimic a meal. For example, the tube feedformula could simulate the appearance of a plate in that it may be acircular, flat package with pictures of meal contents. The patient couldsit down for dinner with a “plate of food.” The add-on package may beany shape or size known in the art and may be sized and shaped tosimulate the appearance of a food item or an eating utensil. In thisway, the tube feeding package would mimic a meal and include an extra,add-on component (e.g., lozenge, dissolvable strip, chewing gum) that,upon opening/consuming, would release a food scent. The patient wouldput the lozenge, dissolvable strip, chewing gum in his/her mouth forflavor. This would allow for a more “natural” eating routine andstimulate the natural response to eating (e.g., the cephalic phase,smell, taste, thought, etc.). The skilled artisan will appreciate thatthe add-on package need not have a particular shape, may have any sizeand shape known in the art, or may be sold separately from the tubefeeding formula.

Benefits of the add-on component relate to simulation of the cephalicphase, and promotion of oral health. Methods of current formula deliveryinclude delivery directly into the GI tract which bypasses this firstphase of digestion, the cephalic phase. The cephalic phase of digestionresults in gastric acid secretion, release of pancreatic enzymesincluding insulin and therefore, may improve digestion and tolerance tothe formula. With bypassing of this first phase of digestion, it couldbe theorized that there are several physiological consequences. First,with bypassing of peristalsis in the esophagus, it could be theorizedthat “pacing” is affected throughout the GI tract. Second, without use,there could be atrophy of the oral/GI muscles which would result indelayed recovery or may be problematic upon resumption of an oral diet.Third, with the discovery of taste receptors in the gut, there may bemissing communication between the mouth and gut taste receptors. Lastly,particularly in diabetic patients and related to early release ofinsulin during the cephalic phase, there may dysregulation in glycemiccontrol

Moreover, the use of the add-on component may also enhance oral health(components including saliva production and oral microbiota) which isimportant for several areas of health, and has been found to be apredictor of mortality. See, Awano S, et al., Oral health and mortalityrisk from pneumonia in the elderly, J. Dent. Res., 87(4):334-339 (2008);Ide R, et al., Oral symptoms predict mortally: a prospective study inJapan, J. Dent. Res. 87(5):485-489 (2008). Patients on tube feedings,for example, are at higher risk for poor oral health and have a higherprevalence reported of gram negative bacteria. See, Leibovitz A, et al.,Saliva secretion and oral flora in prolonged nasogastric tube-fedelderly patients, IMAJ, 5:329-332 (2003). Reduced salivary flow or poororal health are associated with several conditions, which may be commonto individuals on long term tube feedings, including history ofradiation to head and neck, diseases of salivary gland, cystic fibrosis,alcoholic cirrhosis, as well as medication usage includinganticholinergics, antidepressants, antipsychotics, diuretics,antihypertensives, antihistamines, and nonsteroidal anti-inflammatorymedications.

The flavor and scent of the add-on component may or may not be similarto the foods present in the tube feeding. In this manner, the add-oncomponent comes with a variety of flavors for emotional appeal, whichallows the patient to choose what they are hungry for. For example, ifthe tube feed formulation contains chicken, the add-on component maysmell like chicken. The add-on component may have a strong flavor tostimulate saliva production. The strong flavor may be, for example,tart, ginger, etc.

Since the add-on component may be placed directly into the mouth of thepatient, the add-on component may include functional ingredients aswell. For example, the functional ingredients may include probiotics tomaintain healthy oral microflora, or capsaisin to trigger the swallowreflex.

In an embodiment, the dissolvable strip would be used when oral intakeis contraindicated (e.g., dysphagia, neurological impairment).

These types of extra, add-on components may be used when oral intake iscontraindicated and may allow for tube feed formulations that arespecifically designed to mimic the eating process, which primes the bodyto absorb and use nutrients. In an embodiment, the add-on component maybe a flavor tab that is packaged in a wrapper and releases a scent whenopened. The flavor tab may also create a range of flavors for thepatient including, for example, chicken seasoned with parsley, mashedpotatoes, etc. Based on the perceived scents and flavors, the patientcan select what types of flavors they are “hungry” for. In anembodiment, the add-on component (e.g., flavor tab) is used just priorto and during tube feeding administration. The flavor tab can be caloriefree and may only contain ingredients allowed on a Nothing Per Orem(“NPO”) diet.

Physiological feeding includes introduction of routine and variety intothe diet. The idea includes bolus feeding which resembles the breakfast,lunch, dinner, snack pattern in which an enteral formulation is designedto include a variety of food components representative of a varied,mixed, cycle menu diet. A variety of bolus feeding may change dependingon meal or week. The variety of food in the menu cycle may be furtherspecialized and diversified by including ethnic food and various spices.This regimen incorporates benefits of whole food beyond basic nutrientsand provides a source of phyto- and zoo-chemicals with health benefits.The benefits include, but are not limited to oxidative stress modulationwith benefits related to musculoskeletal health, blood pressure,cholesterol levels, glycemic control, cancer, cognitive function,inflammation.

Along these lines, another manner in which to evoke an emotional appealis to provide methods of administering nutritional compositions (e.g.,tube feedings) that mimic regular meal times, or create a cycling menuwith unique foods, as mentioned above. For example, in an embodiment,the tube feed formulations may be administered three times daily atnormal meal times of breakfast, lunch and dinner, and/or with severalsnacks. Similarly, the present compositions may be packaged with anappealing or appetizing label or product name.

In another embodiment, the tube feedings may be administered such thatthe administration creates a cycling menu with unique foods having, forexample, different protein sources, and different fruits and vegetables.The skilled artisan will appreciate that many different combinations ofwhole foods may be used in the present compositions. Different examplesof such combinations include, as with Clinutren Mix products, but arenot limited to, turkey with mixed vegetables, veal with broccoli, springvegetables stew, cod with leek, Hungarian beef, salmon and spinach,chicken and vegetables, and beef and carrots.

In another example, the tube feedings may be administered at normal mealtimes. For example, a first feeding may be administered at a typicalbreakfast time in the morning. A second feeding may be administered at atypical lunch time around noon, and a third feeding may be administeredat a typical dinner time in the evening. The tube feeding formula mayalso be administered at several additional times, mimicking snack times.

The formulation of nutritional compositions of the present disclosuremay be varied from feeding to feeding, day to day, week to week, ormonth to month to provide a patient with a variety of food, whichprovide a variety of different nutrients. For example, daily feedingsmay be varied as follows: a first daily feeding (e.g., at breakfasttime) may be the same as or different from a second daily feeding (e.g.,at lunch time), which may be the same as or different from a third dailyfeeding (e.g., at dinner time). Daily feedings may also vary byproviding a first feeding (e.g., at breakfast time) on day one that isthe same as or different from a first feeding (e.g., at breakfast time)on day two. The same goes for second and third daily feedings.

In another embodiment, feedings may vary from week to week or month tomonth. In this regard, a patient may be administered a specific tubefeed formulation for a week or a month before the formulation changes toa second formulation. Similarly, the patient may be administered a dailyfeeding menu of first, second and third feedings, wherein each firstfeeding is the same for a week or a month, each second feeding is thesame for a week or a month, and each third feeding is the same for aweek or a month before the feedings are changed to a second formulation.

The changing of a first formulation to a second formulation, regardlessof how frequently the formulations are changed, may include changing ofa specific component of the formulation. For example, a tube feedformulation may be administered to a patient on day one that has acertain amounts of protein, carbohydrates and fats. On day two, asimilar tube feed formulation may be administered to the patient thathas the same amount of protein and carbohydrates, but an increased ordecreased amount of fats. In this manner, the amounts of macro andmicronutrients in the nutritional compositions of the present claims mayvary from formula to formula. In an embodiment, at least one source ofprotein of a nutritional composition is different than a new, or second,nutritional composition. In an embodiment, at least one source ofcarbohydrates of a nutritional composition is different than a new, orsecond, nutritional composition. In an embodiment, at least one sourceof fats of a nutritional composition is different than a new, or second,nutritional composition.

The nutritional compositions can be administered to an individual havinga preexisting medical condition, or at risk of developing a medicalcondition, or having characteristics common to patients on long termtube feeding formulas. The underlying medical condition may be, forexample, cerebral palsy, failure-to-thrive, neuromuscular disorders,brain injury, developmental delay, immune deficiency or dysregulation,compromised musculoskeletal and gut health, low bone density, pressureulcers, chronic wounds, insulin resistance, or combinations thereof. Thenutritional composition can be a formulation designed for any mammalsuch as a human or an animal. In an embodiment, the nutritionalcomposition is a tube-feed formulation.

Methods of improving the overall health of a patient having anunderlying medical condition are also provided. The methods includeadministering to a patient having an underlying medical condition a tubefeed formulation having at least five different whole food components, asource of protein, a source of fat, a source of carbohydrate, a sourceof fiber and a source of vitamins or minerals. The formulation includesat least five, six, seven, or eight different whole food components andthe whole food components may be selected from the group consisting of aprocessed fruit, a processed vegetable, a processed meat, a processedgrain, or combinations thereof.

Methods of improving the overall health of a patient having anunderlying medical condition are also provided. The methods includeadministering to a patient having an underlying medical condition a tubefeed formulation having a processed whole food, at least seven differentsources of macronutrients selected from the group consisting of protein,carbohydrates, fats, fibers, or combinations thereof, and a source ofvitamins or minerals. The at least seven different sources ofmacronutrients includes at least one protein, at least one carbohydrateand at least one fat. The at least seven different sources ofmacronutrients may also include at least three different proteins and/orat least three different carbohydrates and/or at least three differentfats.

Methods of administering tube feeding formulations are also provided.The methods include administering a first tube feed formulation having awhole food to a patient at a first time of a day corresponding to atypical breakfast time, administering a second tube feed formulationhaving a whole food to the patient at a second time of the daycorresponding to a typical lunch time, and administering a third tubefeed formulation having a whole food to the patient at a third time ofthe day corresponding to a typical dinner time. The first, second andthird tube feed formulations include at least one protein, and at leastone of a fruit and a vegetable. The protein of each of the first, secondand third tube feed formulations may be different. The at least one of afruit and a vegetable of each of the first, second and third tube feedformulations may also be different. The tube feeding formula may also beadministered at several additional times with different fruits andvegetables and macronutrient sources, mimicking snack times. In thismanner, the methods may include administering fourth, fifth, sixth, etc.formulations correlating with typical daily snack times.

The nutritional compositions of the present claims may be administeredat a temperature that is either warm or cold. It can be theorized thatdifferences in food temperature of a meal containing protein, fat,carbohydrate and whole food components may impact digestion andphysiological response. Indeed, prior research has shown thattemperature (hot, warm, cold) of a simple food beverage, sweetenedinstant coffee, administered via nasogastric tube did not impact gastricacid secretion, serum gastrin concentrations, or gastric emptying. See,K. McArthur, et al., Gastric acid secretion, gastrin release, andgastric emptying in humans as affected by liquid meal temperature, Am.J. Clin. Nutr., 49:51-54 (1989).

The present disclosure also provides tube feed packages. The packagesinclude a first component contained in the package that is a tube feedformulation. The package may resemble the shape of a plate or food itemor combinations thereof. The package further includes a second componentcontained with or attached to the first component, or purchasedseparately. The second component is comprised of a substance that isconsumed by mouth and has a flavor/taste and an aroma and being packagedseparately from the first component. The second component may be atablet or lozenge, dissolvable strip or chewing gum and would betailored to be NPO-compliant when necessary and may be contained in apackage of a particular size or shape.

By using the improved compositions and methods of administering same,Applicant is able to provide improved nutritional compositions to adultand pediatric patients that have an increased number and variety offruits and vegetables, an increased variety of macronutrient sources,and the addition of other components found in whole foods. The improvedformulations help to mimic a “whole food” tube feeding that best meetsthe nutritional needs of the target population and also providesphysiological benefits and emotional appeal.

It should be understood that various changes and modifications to thepresently preferred embodiments described herein will be apparent tothose skilled in the art. Such changes and modifications can be madewithout departing from the spirit and scope of the present subjectmatter and without diminishing its intended advantages. It is thereforeintended that such changes and modifications be covered by the appendedclaims.

The invention is claimed as follows:
 1. A tube feed package comprising:a first component contained in a first package and comprising a tubefeed formulation having a processed whole food, the first componenthaving an osmolality up to 400 mOsm/kg water; and a second componentcontained in a second package that is separate from the first package ofthe first component, the second component being an orally dissolvablestrip.
 2. The tube feed package according to claim 1, wherein the flavorof the second component corresponds to the processed whole food of thetube feed formulation.
 3. The tube feed package according to claim 1,wherein the flavor and/or scent of the second component corresponds to anutrient source that is typically consumed by individuals in a specificregion of the world.
 4. The tube feed package according to claim 1,wherein the second component is compliant with a nothing per orem(“NPO”) diet.
 5. The tube feed package according to claim 1, wherein thesecond component includes a functional ingredient selected from thegroup consisting of probiotics, capsaisin, a source of strong flavor,and combinations thereof.
 6. The tube feed package according to claim 5,wherein the strong flavor is one of tart and ginger.
 7. The tube feedpackage according to claim 1, wherein the second component is containedin a package having a shape of an eating utensil selected from the groupconsisting of a plate, a spoon, a fork, a knife, and combinationsthereof.
 8. The tube feed package according to claim 1, wherein thesecond component is calorie free.
 9. A tube feed package comprising: afirst component contained in a first package and comprising a tube feedformulation having a processed whole food, the first component having anosmolality up to 400 mOsm/kg water; and a second component packaged in asecond package that is separate from the first package of the firstcomponent for placing into a mouth of a patient, the second componentbeing an orally dissolvable strip and comprising a substance having anaroma.
 10. The tube feed package according to claim 9, wherein thesecond component is not edible.
 11. The tube feed package according toclaim 9, wherein the aroma of the second component corresponds to atypical aroma of the processed whole food of the tube feed formulation.12. The tube feed package according to claim 9, wherein the aroma of thesecond component corresponds to a nutrient source that is typicallyconsumed by individuals in a specific region of the world.